Cycloalkyl pyrimidines as ferroportin inhibitors

ABSTRACT

The subject matter described herein is directed to ferroportin inhibitor compounds of Formula I or I′ and pharmaceutical salts thereof, methods of preparing the compounds, pharmaceutical compositions comprising the compounds, and methods of administering the compounds for prophylaxis and/or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, particularly iron overload states, such as thalassemia, sickle cell disease and hemochromatosis, and also kidney injuries.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalApplication No. 63/016,891, filed on Apr. 28, 2020, and U.S. ProvisionalApplication No. 63/127,774, filed on Dec. 18, 2020, the contents of eachof which are hereby incorporated by reference in their entirety.

FIELD

The subject matter described herein is directed to ferroportin inhibitorcompounds, methods of making the compounds, their pharmaceuticalcompositions, and their use in the prophylaxis and/or treatment ofdiseases caused by a lack of hepcidin or iron metabolism disorders,particularly iron overload states, such as thalassemia, sickle celldisease and hemochromatosis, and also kidney injuries.

BACKGROUND

In nearly all organisms, iron is an essential trace element. In humans,iron is a critical component for oxygen transport, oxygen uptake, cellfunctions such as mitochondrial electron transport, cognitive functions,and energy metabolism. Iron is present in enzymes, hemoglobin andmyoglobin, as well as in depots in the form of ferritin and hemosiderin.With respect to hemoglobin, approximately half of all iron is present asheme iron, bound in the hemoglobin of the erythrocytes. The human bodycontains on average approximately 4 to 5 g iron. The iron requirement ofa human adult is between 0.5 to 1.5 mg per day, whereas infants andwomen during pregnancy require 2 to 5 mg of iron per day.

In a healthy human adult, the normal daily loss of iron of about 1 mg isusually replaced via food intake. Iron balance is primarily regulated byrecycling and iron recovery from hemoglobin of aging erythrocytes andthe duodenal absorption of dietary iron in the form of divalent as wellas trivalent iron ions.

Absorption is regulated by the organism depending on the ironrequirement and the size of the iron depot. Usually, Fe(III) compoundsare dissolved in the stomach at a sufficiently acidic pH value and thusmade available for absorption. The absorption of the iron is carried outin the upper small intestine by mucosal cells. Trivalent non-heme ironis first reduced in the intestinal cell membrane to Fe(II) forabsorption, for example by ferric reductase (membrane-bound duodenalcytochrome b), so that it can then be transported into the intestinalcells by means of the transport protein DMT1 (divalent metal transporter1). In contrast, heme iron enters the enterocytes through the cellmembrane without any change. In the enterocytes, iron is either storedin ferritin as depot iron, or released into the blood by the transportprotein ferroportin. The divalent iron transported into the blood byferroportin is converted into trivalent iron by oxidases (ceruloplasmin,hephaestin). The trivalent iron is then transported to its destinationin the organism by transferrin. (“Balancing acts: molecular control ofmammalian iron metabolism,” M. W. Hentze, Cell, 1:17, 2004, 285-297).Hepcidin plays a central role in this process because it is theessential regulating factor of iron absorption. The hepcidin-ferroportinsystem directly regulates iron metabolism.

Iron uptake and storage is regulated by hepcidin. Hepcidin AntimicrobialPeptide (HAMP; also known as LEAP-1; further referred to as Hepcidin) isa 25 amino acid peptide (Krause et al., FEBS Lett. 480, 147-150, 2000).Hepcidin has a hairpin structure with 8 cysteines that form 4 disulfidebridges (Jordan et al., J Biol Chem. 284, 24155-24167, 2009). TheN-terminus appears to be important for the iron-regulatory functionsince deletion of the first 5 amino acids resulted in complete loss ofbioactivity (Nemeth et al., Blood, 107, 328-333, 2006). Hepcidin isproduced in the liver and functions as the master iron regulatoryhormone controlling intestinal iron uptake, and also regulates ironstorage in other organs (Ganz, Hematol. Am.

Soc. Hematol. Educ. Program, 29-35, 507 2006; Hunter et al., J. Biol.Chem. 277, 37597-37603, 2002; Park et al., J. Biol. Chem. 276,7806-7810, 2001). Hepcidin limits iron-uptake by binding to the irontransport molecule ferroportin and causing its degradation (Sebastianiet al., Front. Pharmacol. 7, 160, 2016).

The formation of hepcidin is regulated in direct correlation to theorganism's iron level, i.e., if the organism is supplied with sufficientiron and oxygen, more hepcidin is formed; if iron and oxygen levels arelow, or in case of increased erythropoiesis, less hepcidin is formed. Inthe small intestinal mucosal cells and in the macrophages hepcidin bindswith the transport protein ferroportin, which conventionally transportsthe phagocytotically recycled iron from the interior of the cell intothe blood.

Ferroportin is an iron transporter that plays a key role in regulatingiron uptake and distribution in the body and thus in controlling ironlevels in the blood. The transport protein ferroportin is atransmembrane protein consisting of 571 amino acids which is formed inthe liver, spleen, kidneys, heart, intestine and placenta. Inparticular, ferroportin is localized in the basolateral membrane ofintestinal epithelial cells. Ferroportin bound in this way thus acts toexport the iron into the blood. In this case, it is most probable thatferroportin transports iron as Fe²⁺. If hepcidin binds to ferroportin,ferroportin is transported into the interior of the cell, where itsbreakdown takes place so that the release of the phagocytoticallyrecycled iron from the cells is then almost completely blocked. If theferroportin is inactivated, for example by hepcidin, so that it isunable to export the iron which is stored in the mucosal cells, thestored iron is lost with the natural shedding of cells via the stools.The absorption of iron in the intestine is therefore reduced, whenferroportin is inactivated or inhibited, for example by hepcidin.

A decrease of hepcidin results in an increase of active ferroportin,thus allowing an enhanced release of stored iron and an enhanced ironuptake, e.g., from the food, resulting in an increase in serum ironlevels, i.e., iron overload. Iron overload causes many diseases andundesired medical conditions. Iron overload can be treated by removal ofthe iron from the body. This treatment includes regularly scheduledphlebotomies (bloodletting). For patients unable to tolerate routineblood draws, there are chelating agents available for use. Adisadvantage in the treatment of iron overload by chelation therapy isthe removal of the chelated iron from the body when the iron overloadhas already occurred instead of preventing the occurrence of thedisorder.

What is therefore needed and not effectively addressed by the art arecompounds that act as ferroportin inhibitors that have desired efficacyand therapeutic potential. This problem as well as others stemming fromiron imbalance are addressed by the subject matter described herein.

BRIEF SUMMARY

In certain embodiments, the subject matter described herein is directedto a compound of Formula I or Formula I′ or a pharmaceuticallyacceptable salt thereof.

In certain embodiments, the subject matter described herein is directedto a pharmaceutical composition comprising a compound of Formula I orFormula I′ or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject matter described herein is directedto methods of inhibiting iron transport mediated by ferroportin in asubject, comprising administering to the subject an effective amount ofa compound of Formula I or Formula I′, a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition comprising a compound ofFormula I or Formula I′.

In certain embodiments, the subject matter described herein is directedto methods of preparing compounds of Formula I or Formula I′.

Other embodiments are also described.

DETAILED DESCRIPTION

Described herein are ferroportin inhibitor compounds of Formula I andFormula I′, methods of making the compounds, pharmaceutical compositionscomprising the compounds and their use in the prophylaxis and/ortreatment of diseases caused by a lack of hepcidin or iron metabolismdisorders, particularly iron overload states, such as thalassemia,sickle cell disease and hemochromatosis. Ferroportin is the irontransport protein responsible for the uptake of the released iron viathe intestine and its transfer into the blood circulation, whereultimately the iron is delivered to the appropriate tissues and organs.Inactivation or inhibition of the ferroportin reduces or prevents theexport of the iron, thereby reducing the absorption of iron in theintestine and ultimately the amount of iron in the body. Thesecompounds, compositions and methods can be used for an effective therapyfor the prophylaxis and treatment of iron metabolism disorders which areassociated with increased iron levels. It is desirable to providecompounds, compositions and methods that exhibit few side effects, havevery low toxicity and good bioavailability and compatibility.

Iron overload has been associated with a variety of diseases (Blanchetteet al., Expert Rev. Hematol. 9, 169-186, 2016). Hereditaryhemochromatosis is the most common inherited disease in Europe and iscaused by lack of, or insensitivity to, hepcidin (Powell et al., TheLancet 388, 706-716, 2016). The clinical manifestation ofhemochromatosis are hepatic cirrhosis, diabetes, and skin pigmentation(Powell et al., The Lancet 388, 706-716, 2016). While this disease canbe managed by phlebotomy, this approach may be cumbersome and does nottreat the cause of the disease.

Iron-loading anemias such as beta-thalassemia are also associated withreduced hepcidin levels (Origa et al., Haematologica 92, 583-588, 2007).Treatment of this disease with hepcidin mimetics may not only addressthe iron overload, but has also been shown to improve the ineffectiveerythropoiesis that occurs in this disease (Casu et al., Blood 128,265-276, 2016). This may be of major benefit for thalassemia patientswho may be less dependent on blood transfusions, which can contribute tothe iron overload in these patients.

Myelofibrosis, myelodysplastic syndrome, and sickle cell disease arediseases that are also characterized by ineffective erythropoiesis andthat may require frequent blood transfusions (Carreau et al., Blood Rev.30, 349-356, 2016; Temraz et al., Crit. Rev. Oncol. Hematol. 91, 64-73,2014; Walter et al., Acta Haematol. 122, 174-183, 2009). Reducedhepcidin levels have been described in some of these patients (Cui etal., Leuk. Res. 38, 545-550, 2014; Santini et al., PLoS ONE 6, e23109,2011). Hepcidin mimetics may also be beneficial in these patients.

Polycythemia vera is a disease characterized by increasederythropoiesis. It has been shown in animal models that high doses ofhepcidin mimetics can ameliorate this disease by diminishingerythropoiesis (Casu et al., Blood 128, 265-276, 2016).

Reduction of iron uptake and thereby serum iron levels may even bebeneficial in diseases where iron load is normal, such as kidneydiseases (Walker and Agarwal, Nephrol. 36, 62-70, 2016), infections withiron-dependent bacteria (Arezes et al., Cell Host Microbe 17, 47-57,2015), and polymicrobial sepsis (Zeng et al., Anesthesiology, 122,374-386, 2015).

Hepcidin itself is limited in its use as a drug because of its complexstructure which requires a complicated manufacturing, and also itslimited in vivo duration of action. Continuous efforts have been made tosearch for hepcidin mimetics and chemical compounds that could be usedto increase hepcidin levels.

A common approach relates to small hepcidin-derived or hepcidin-likepeptides, which can be produced affordably, and can be used to treathepcidin-related diseases and disorders such as those described herein.Such so-called mini-hepcidins are rationally designed small peptidesthat mimic hepcidin activity and may be useful for the treatment of ironoverload, and also iron overload related disease symptoms.

Such mini-hepcidin peptides are described for example in WO 2010/065815A2 and WO 2013/086143 A1. WO 2015/157283 A1 and the corresponding U.S.Pat. No. 9,315,545 B2 describe hepcidin mimetic peptides and the usethereof in hepcidin-related disorders, such as iron overload,beta-thalassemia, hemochromatosis etc. and cover a development compoundM012 of the company Merganser Biotech, having been under evaluation in aPhase 1 clinical program as a potentially transformative therapy for anumber of hematological diseases including beta-thalassemia, low riskmyelodysplasia and polycythemia vera.

WO 2014/145561 A2 and WO 2015/200916 A2 describe further small hepcidinpeptide analogues and the use thereof in the treatment or prevention ofa variety of hepcidin-related diseases, including iron overload diseasesand iron-loading anemias, and further related disorders. Further,WO2015/042515 A1 relates to hepcidin and its peptide fragments, whichare particularly intended for treating renal ischemia reperfusion injuryor acute kidney injury. Further, mini-hepcidin analogs are described forexample by Preza et al., J. Clin. Invest., 121 (12), 4880-4888, 2011 orin CN 104 011 066 and in WO 2016/109363 A1.

Ferroportin inhibitors as well as compounds that have hepcidin-likeactivity are needed that also possess additional beneficial propertiessuch as improved solubility, stability, and/or potency. An advantage ofthe ferroportin inhibitor compounds of Formula I described herein istheir preparation in sufficient yields by the synthetic routes disclosedherein.

The presently disclosed subject matter will now be described more fullyhereinafter. However, many modifications and other embodiments of thepresently disclosed subject matter set forth herein will come to mind toone skilled in the art to which the presently disclosed subject matterpertains having the benefit of the teachings presented in the foregoingdescriptions. Therefore, it is to be understood that the presentlydisclosed subject matter is not to be limited to the specificembodiments disclosed and that modifications and other embodiments areintended to be included within the scope of the appended claims. Inother words, the subject matter described herein covers allalternatives, modifications, and equivalents. Unless otherwise defined,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in this field. Allpublications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety. In theevent that one or more of the incorporated literature, patents, andsimilar materials differs from or contradicts this application,including but not limited to defined terms, term usage, describedtechniques, or the like, this application controls.

I. Definitions

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —C(O)NH₂is attached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line or a dashed line drawn through orperpendicular across the end of a line in a structure indicates aspecified point of attachment of a group. Unless chemically orstructurally required, no directionality or stereochemistry is indicatedor implied by the order in which a chemical group is written or named.

The prefix “C_(u)-C_(v)” indicates that the following group has from uto v carbon atoms. For example, “C₁-C₆ alkyl” indicates that the alkylgroup has from 1 to 6 carbon atoms.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount±50%. In certain other embodiments, the term “about” includes theindicated amount±20%. In certain other embodiments, the term “about”includes the indicated amount±10%. In other embodiments, the term“about” includes the indicated amount±5%. In certain other embodiments,the term “about” includes the indicated amount±1%. In certain otherembodiments, the term “about” includes the indicated amount±0.5% and incertain other embodiments, 0.1%. Such variations are appropriate toperform the disclosed methods or employ the disclosed compositions.Also, to the term “about x” includes description of “x”. Also, thesingular forms “a” and “the” include plural references unless thecontext clearly dictates otherwise. Thus, e.g., reference to “thecompound” includes a plurality of such compounds and reference to “theassay” includes reference to one or more assays and equivalents thereofknown to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁-C₂₀ alkyl), 1to 12 carbon atoms (i.e., C₁-C₁₂ alkyl), 1 to 8 carbon atoms (i.e.,C₁-C₈ alkyl), 1 to 6 carbon atoms (i.e., C₁-C₆ alkyl), 1 to 4 carbonatoms (i.e., C₁-C₄ alkyl), or 1 to 3 carbon atoms (i.e., C₁-C₃ alkyl).Examples of alkyl groups include, e.g., methyl, ethyl, propyl,isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl,isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. Whenan alkyl residue having a specific number of carbons is named bychemical name or identified by molecular formula, all positional isomershaving that number of carbons may be encompassed; thus, for example,“butyl” includes n-butyl (i.e., —(CH₂)₃CH₃), sec-butyl (i.e.,—CH(CH₃)CH₂CH₃), isobutyl (i.e., —CH₂CH(CH₃)₂) and tert-butyl (i.e.,—C(CH₃)₃); and “propyl” includes n-propyl (i.e., —(CH₂)₂CH₃) andisopropyl (i.e., —CH(CH₃)₂).

Certain commonly used alternative chemical names may be used. Forexample, a divalent group such as a divalent “alkyl” group, a divalent“aryl” group, etc., may also be referred to as an “alkylene” group or an“alkylenyl” group, an “arylene” group or an “arylenyl” group,respectively. Also, unless indicated explicitly otherwise, wherecombinations of groups are referred to herein as one moiety, e.g.,arylalkyl or aralkyl, the last mentioned group contains the atom bywhich the moiety is attached to the rest of the molecule.

“Alkenyl” refers to an alkyl group containing at least one carbon-carbondouble bond and having from 2 to 20 carbon atoms (i.e., C₂-C₂₀ alkenyl),2 to 8 carbon atoms (i.e., C₂-C₈ alkenyl), 2 to 6 carbon atoms (i.e.,C₂-C₆ alkenyl) or 2 to 4 carbon atoms (i.e., C₂-C₄ alkenyl). Examples ofalkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an alkyl group containing at least one carbon-carbontriple bond and having from 2 to 20 carbon atoms (i.e., C₂-C₂₀ alkynyl),2 to 8 carbon atoms (i.e., C₂-C₈ alkynyl), 2 to 6 carbon atoms (i.e.,C₂-C₆ alkynyl) or 2 to 4 carbon atoms (i.e., C₂-C₄ alkynyl). The term“alkynyl” also includes those groups having one triple bond and onedouble bond.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, such as, methylene —CH₂—,ethylene —CH₂CH₂—, and the like. As an example, a “hydroxy-methylene”refers to HO—CH₂—*, where * is the attachment point to the molecule.

“Alkoxy” refers to the group “alkyl-O—” (e.g., C₁-C₃ alkoxy or C₁-C₆alkoxy). Examples of alkoxy groups include, e.g., methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexoxy and 1,2-dimethylbutoxy.

“Alkoxy-alkyl” refers to the group “-alkyl-alkoxy”. The term “C₁-C₃alkoxy-C₁-C₃ alkyl” refers to a one to three carbon alkyl chain whereone hydrogen on any carbon is replaced by an alkoxy group having one tothree carbons, in particular, one hydrogen on one carbon of the alkylchain is replaced by an alkoxy group having one to three carbons. Theterm, “C₁-C₆ alkoxy-C₁-C₃ alkyl” refers to a one to three carbon alkylchain where one hydrogen on any carbon is replaced by an alkoxy grouphaving one to six carbons, in particular, one hydrogen on one carbon ofthe alkyl chain is replaced by an alkoxy group having one to sixcarbons. Non-limiting examples of alkoxy-alkyl are —CH₂OCH₃,—CH₂OC(CH₃)₃, and —C(CH₃)₂CH₂OCH₃.

“Alkylthio” refers to the group “alkyl-S—”. “Alkylthioalkyl” refers tothe group -alkyl-S-alkyl, such as —C₁-C₃-alkyl-S—C₁-C₃ alkyl. Anon-limiting example of alkylthioalkyl is —CH₂CH₂SCH₃. “Alkylsulfinyl”refers to the group “alkyl-S(O)—”. “Alkylsulfonyl” refers to the group“alkyl-S(O)₂—”. “Alkylsulfonylalkyl” refers to -alkyl-S(O)₂-alkyl.

“Acyl” refers to a group —C(O)R^(y), wherein R^(y) is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of acyl include, e.g., formyl, acetyl,cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group—C(O)NR^(y)R^(z) and an “N-amido” group which refers to the group—NR^(y)C(O)R^(z), wherein R^(y) and R^(z) are independently hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl orheteroaryl; each of which may be optionally substituted, as definedherein, or R^(y) and R^(z) are taken together to form a cycloalkyl orheterocyclyl; each of which may be optionally substituted, as definedherein.

“Amino” refers to the group —NR^(y)R^(z) wherein R^(y) and R^(z) areindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Amidino” refers to —C(NR^(y))(NR^(z) ₂), wherein R^(y) and R^(z) areindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆-C₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆-C₁₂aryl), or 6 to 10 carbon ring atoms (i.e., C₆-C₁₀ aryl). Examples ofaryl groups include, e.g., phenyl, naphthyl, fluorenyl and anthryl.Aryl, however, does not encompass or overlap in any way with heteroaryldefined below. If one or more aryl groups are fused with a heteroaryl,the resulting ring system is heteroaryl regardless of the point ofattachment. If one or more aryl groups are fused with a heterocyclyl,the resulting ring system is heterocyclyl regardless of the point ofattachment.

“Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-”, such as(C₆-C₁₀ aryl)-C₁-C₃ alkyl. As used herein, “(C₆-C₁₀ aryl)-C₁-C₃ alkyl”refers to a one to three carbon alkyl chain where one of the hydrogenatoms on any carbon is replaced by an aryl group having six to tencarbon atoms, in particular, one hydrogen on one carbon of the alkylchain is replaced by an aryl group having six to ten carbon atoms. Anon-limiting example of arylalkyl is benzyl.

“Carbamoyl” refers to both an “O-carbamoyl” group which refers to thegroup —O—C(O)NR^(y)R^(z) and an “N-carbamoyl” group which refers to thegroup —NR^(y)C(O)OR^(z), wherein R^(y) and R^(z) are independentlyhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl or heteroaryl; each of which may be optionally substituted,as defined herein.

“Carboxyl ester” or “ester” refer to both —OC(O)R^(x) and —C(O)OR^(x),wherein R^(x) is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, heteroalkyl or heteroaryl; each of which may be optionallysubstituted, as defined herein.

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkylgroup having a single ring or multiple rings including fused, bridgedand spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e., the cyclic group having at least one double bond) andcarbocyclic fused ring systems having at least one sp³ carbon atom(i.e., at least one non-aromatic ring). As used herein, cycloalkyl hasfrom 3 to 20 ring carbon atoms (i.e., C₃-C₂₀ cycloalkyl), 3 to 12 ringcarbon atoms (i.e., C₃-C₁₂ cycloalkyl), 3 to 10 ring carbon atoms (i.e.,C₃-C₁₀ cycloalkyl), 3 to 8 ring carbon atoms (i.e., C₃-C₈ cycloalkyl), 3to 7 ring carbon atoms (i.e., C₃-C₇ cycloalkyl), or 3 to 6 ring carbonatoms (i.e., C₃-C₆ cycloalkyl). Monocyclic groups include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. Polycyclic groups include, for example, bridged and/or fusedrings, such as bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl,bicyclo[1.1.1]pentan-1-yl, adamantyl, norbornyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl and the like. Further, the termcycloalkyl is intended to encompass any ring or ring system comprising anon-aromatic alkyl ring which may be fused to an aryl ring, regardlessof the attachment to the remainder of the molecule. Further, cycloalkylalso includes “spirocycloalkyl” when there are two positions forsubstitution on the same carbon atom, for example spiro[2.5]octanyl,spiro[4.5]decanyl, or spiro[5.5]undecanyl.

“Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”, such as(C₃-C₆ cycloalkyl)-C₁-C₃ alkyl. As used herein, “(C₃-C₆cycloalkyl)-C₁-C₃ alkyl” refers to a one to three carbon alkyl chainwhere one of the hydrogen atoms on any carbon is replaced by acycloalkyl group having three to six carbon atoms, in particular, onehydrogen on one carbon of the chain is replaced by a cycloalkyl grouphaving three to six carbon atoms.

“Cycloalkyl-alkoxy” refers to the group “-alkoxy-cycloalkyl” (e.g.,C₃-C₇ cycloalkyl-C₁-C₆ alkoxy- or C₃-C₇ cycloalkyl-C₁-C₃ alkoxy-), suchas —OCH₂-cyclopropyl. As used herein, “C₃-C₇ cycloalkyl-C₁-C₆ alkoxy”refers to an alkoxy group having a one to six carbon alkyl chain,wherein one of the hydrogen atoms on any carbon is replaced by acycloalkyl group having three to seven carbon atoms, in particular, onehydrogen on one carbon of the chain is replaced by a cycloalkyl grouphaving three to seven carbon atoms. As used herein, “C₃-C₇cycloalkyl-C₁-C₃ alkoxy” refers to an alkoxy group having a one to threecarbon alkyl chain, wherein one of the hydrogen atoms on any carbon isreplaced by a cycloalkyl group having three to seven carbon atoms, inparticular, one hydrogen on one carbon of the chain is replaced by acycloalkyl group having three to seven carbon atoms.

“Guanidino” refers to —NR^(y)C(═NR^(z))(NR^(y)R^(z)), wherein each R^(y)and R^(z) are independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of whichmay be optionally substituted, as defined herein.

“Hydrazino” refers to —NHNH₂.

“Imino” refers to a group —C(NR^(y))R^(z), wherein R^(y) and R^(z) areeach independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Imido” refers to a group —C(O)NR^(y)C(O)R^(z), wherein R^(y) and R^(z)are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Halogen” or “halo” refers to atoms occupying group VIIA of the periodictable, such as fluoro (fluorine), chloro (chlorine), bromo (bromine) oriodo (iodine).

“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms arereplaced by a halogen. For example, halo-C₁-C₃ alkyl refers to an alkylgroup of 1 to 3 carbons wherein at least one hydrogen atom is replacedby a halogen. Where a residue is substituted with more than one halogen,it may be referred to by using a prefix corresponding to the number ofhalogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may be,but are not necessarily, the same halogen. Examples of haloalkylinclude, e.g., trifluoromethyl, difluoromethyl, fluoromethyl,trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl,3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like.

“Haloalkoxy” refers to an alkoxy group as defined above, wherein one ormore (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a halogen.Non-limiting examples of haloalkoxy are —OCH₂CF₃, —OCF₂H, and —OCF₃.

“Hydroxyalkyl” refers to an alkyl group as defined above, wherein one ormore (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a hydroxygroup (e.g., hydroxy-C₁-C₃-alkyl, hydroxy-C₁-C₆-alkyl). The term“hydroxy-C₁-C₃ alkyl” refers to a one to three carbon alkyl chain whereone or more hydrogens on any carbon is replaced by a hydroxy group, inparticular, one hydrogen on one carbon of the chain is replaced by ahydroxy group. The term “hydroxy-C₁-C₆ alkyl” refers to a one to sixcarbon alkyl chain where one or more hydrogens on any carbon is replacedby a hydroxy group, in particular, one hydrogen on one carbon of thechain is replaced by a hydroxy group. Non-limiting examples ofhydroxyalkyl include —CH₂OH, —CH₂CH₂OH, and —C(CH₃)₂CH₂OH.

“Hydroxyalkoxy” refers to the group “-alkoxy-hydroxy,” (e.g.,hydroxy-C₁-C₃ alkoxy, hydroxy-C₁-C₆ alkoxy). The term “hydroxy-C₁-C₃alkoxy” refers to an alkoxy group containing a one to three carbon alkylchain wherein one or more hydrogens on any carbon is replaced by ahydroxy group, in particular, one hydrogen on one carbon of the chain isreplaced by a hydroxy group. The term “hydroxy-C₁-C₆ alkoxy” refers toan alkoxy group containing a one to six carbon alkyl chain wherein oneor more hydrogens on any carbon is replaced by a hydroxy group, inparticular, one hydrogen on one carbon of the chain is replaced by ahydroxy group. Non-limiting examples of hydroxyalkoxy include —OCH₂CH₂OHand —OCH₂C(CH₃)₂OH.

“Heteroalkyl” refers to an alkyl group in which one or more of thecarbon atoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatomic group, provided thepoint of attachment to the remainder of the molecule is through a carbonatom. In certain embodiments, the heteroalkyl can have 1 to 3 carbonatoms (e.g., C₁-C₃ heteroalkyl) or 1 to 6 carbon atoms (e.g., C₁-C₆heteroalkyl), and one or more (e.g., 1, 2, or 3) heteroatoms orheteroatomic groups. The term “heteroalkyl” includes unbranched orbranched saturated chain having carbon and heteroatoms. By way ofexample, 1, 2 or 3 carbon atoms of the alkyl group in the “heteroalkyl”may be independently replaced with the same or different heteroatomicgroup. Heteroatomic groups include, but are not limited to, —NR^(y)—,—O—, —S—, —S(O)—, —S(O)₂—, and the like, wherein R is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of heteroalkyl groups include, e.g., ethers (e.g.,—CH₂OCH₃, —CH(CH₃)OCH₃, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₂OCH₃, etc.),thioethers (e.g., —CH₂SCH₃, —CH(CH₃)SCH₃, —CH₂CH₂SCH₃,—CH₂CH₂SCH₂CH₂SCH₃, etc.), sulfones (e.g., —CH₂S(O)₂CH₃,—CH(CH₃)S(O)₂CH₃, —CH₂CH₂S(O)₂CH₃, —CH₂CH₂S(O)₂CH₂CH₂OCH₃, etc.) andamines (e.g., —CH₂NR^(y)CH₃, —CH(CH₃)NR^(y)CH₃, —CH₂CH₂NR^(y)CH₃,—CH₂CH₂NR^(y)CH₂CH₂NR^(y)CH₃, etc., where R^(y) is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein). In certain embodiments, heteroalkyl can have 1 to 20 carbonatoms, 1 to 15 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms,1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1to 2 heteroatoms, or 1 heteroatom.

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur. As usedherein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C₁-C₂₀heteroaryl), 3 to 12 ring carbon atoms (i.e., C₃-C₁₂ heteroaryl), or 3to 8 carbon ring atoms (i.e., C₃-C₈ heteroaryl), and 1 to 5 ringheteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2ring heteroatoms, or 1 ring heteroatom independently selected fromnitrogen, oxygen and sulfur. In certain instances, heteroaryl includes9-10 membered ring systems (i.e., 9-10 membered heteroaryl), 5-10membered ring systems (i.e., 5-10 membered heteroaryl), 5-7 memberedring systems (i.e., 5-7 membered heteroaryl), 5-6 membered ring systems(i.e., 5-6 membered heteroaryl), or 4-6 membered ring systems (i.e., 4-6membered heteroaryl), each independently having 1 to 4 ring heteroatoms,1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatomindependently selected from nitrogen, oxygen and sulfur. Examples ofheteroaryl groups include, e.g., acridinyl, benzimidazolyl,benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl,benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl,isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl,1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl,pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl. Examplesof the fused-heteroaryl rings include, but are not limited to,benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl,indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl andimidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via eitherring of the fused system. Any aromatic ring or ring system, having asingle or multiple fused rings, containing at least one heteroatom, isconsidered a heteroaryl regardless of the attachment to the remainder ofthe molecule (i.e., through any one of the fused rings). Heteroaryl doesnot encompass or overlap with aryl as defined above.

“Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”, such as (5-to 10-membered monocyclic heteroaryl)-C₁-C₃ alkyl. As used, herein, “(5-to 10-membered monocyclic heteroaryl)-C₁-C₃ alkyl” refers to a one tothree carbon alkyl chain where one or more hydrogens on any carbon isreplaced by a monocyclic heteroaryl group having 5- to 10-members, inparticular, one hydrogen on one carbon of the chain is replaced by a (5-to 10-membered monocyclic heteroaryl group.

“Heterocyclyl” refers to a saturated or partially unsaturated cyclicalkyl group, with one or more ring heteroatoms independently selectedfrom nitrogen, oxygen and sulfur. The term “heterocyclyl” includesheterocycloalkenyl groups (i.e., the heterocyclyl group having at leastone double bond), bridged-heterocyclyl groups, fused-heterocyclyl groupsand spiro-heterocyclyl groups. A heterocyclyl may be a single ring ormultiple rings wherein the multiple rings may be fused, bridged orspiro. Any non-aromatic ring containing at least one heteroatom isconsidered a heterocyclyl, regardless of the attachment (i.e., can bebound through a carbon atom or a heteroatom). Further, the termheterocyclyl is intended to encompass a ring or ring system comprisingany non-aromatic ring containing at least one heteroatom, which ring maybe fused to an aryl or heteroaryl ring, regardless of the attachment tothe remainder of the molecule. The term heterocyclyl is also intended toencompass a ring system comprising a cycloalkyl ring which is fused to aheteroaryl ring, regardless of the attachment to the remainder of themolecule. Additionally, the term heterocyclyl is intended to encompass aring system comprising a cycloalkyl ring which is fused to aheterocyclyl ring, regardless of the attachment to the remainder of themolecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms(i.e., C₂-C₂₀ heterocyclyl), 2 to 12 ring carbon atoms (i.e., C₂-C₁₂heterocyclyl), 2 to 10 ring carbon atoms (i.e., C₂-C₁₀ heterocyclyl), 2to 8 ring carbon atoms (i.e., C₂-C₈ heterocyclyl), 3 to 12 ring carbonatoms (i.e., C₃-C₁₂ heterocyclyl), 3 to 8 ring carbon atoms (i.e., C₃-C₈heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C₃-C₆ heterocyclyl);having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ringheteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independentlyselected from nitrogen, sulfur or oxygen. When the heterocyclyl ringcontains 4- to 6-ring atoms, it is also referred to herein as a 4- to6-membered heterocyclyl. Also disclosed herein are 5- or 6-memberedheterocyclyls, having 5 or 6 ring atoms, respectively, and 5- to10-membered heterocyclyls, having 5 to 10 ring atoms. Examples ofheterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl,benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl,hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl,imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl,isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl,phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl,pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl,tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e.,thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. In certainembodiments, the term “heterocyclyl” can include “spiroheterocyclyl”when there are two positions for substitution on the same carbon atom.Examples of the spiro-heterocyclyl rings include, e.g., bicyclic andtricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl,2-oxa-6-azaspiro[3.4]octanyl and 6-oxa-1-azaspiro[3.3]heptanyl. Examplesof the fused-heterocyclyl rings include, but are not limited to,1,2,3,4-tetrahydroisoquinolinyl,4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl,where the heterocyclyl can be bound via either ring of the fused system.

“Heterocyclylalkyl” refers to the group “heterocyclyl-alkyl-.”

“Oxime” refers to the group —CR^(y)(═NOH) wherein R^(y) is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl orheteroaryl; each of which may be optionally substituted, as definedherein.

“Oxo” refers to the group (═O).

“Sulfonyl” refers to the group —S(O)₂R^(y), where R^(y) is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl,phenylsulfonyl and toluenesulfonyl.

“Sulfinyl” refers to the group —S(O)R^(y), where R^(y) is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl,phenylsulfinyl and toluenesulfinyl.

“Sulfonamido” refers to the groups —SO₂NR^(y)R^(z) and —NR^(y)SO₂R^(z),where R^(y) and R^(z) are each independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; eachof which may be optionally substituted, as defined herein.

The terms “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” refers to any one or more (e.g., 1 to 5, 1 to 4, or 1 to 3)hydrogen atoms on the designated atom or group may or may not bereplaced by a moiety other than hydrogen.

The term “substituted” used herein means any of the above groups (i.e.,alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy,cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) whereinat least one (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atom is replacedby a bond to a non-hydrogen atom such as, but not limited to alkyl,alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl,aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl,cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, —NHNH₂, ═NNH₂, imino, imido, hydroxy, oxo, oxime,nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate,—S(O)OH, —S(O)₂OH, sulfonamido, thiol, thioxo, N-oxide or —Si(R^(y))₃,wherein each R^(y) is independently hydrogen, alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl.

In certain embodiments, “substituted” includes any of the above alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups inwhich one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms areindependently replaced with deuterium, halo, cyano, nitro, azido, oxo,alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, —NR^(g)R^(h), —NR^(g)C(═O)R^(h), —NR^(g)C(═O)NR^(g)R^(h),—NR^(g)C(═O)OR^(h), —NR^(g)S(═O)₁₋₂R^(h), —C(═O)R^(g), —C(═O)OR^(g),—OC(═O)OR^(g), —OC(═O)R^(g), —C(═O)NR^(g)R^(h), —OC(═O)NR^(g)R^(h),—OR^(g), —SR^(g), —S(═O)R^(g), —S(═O)₂R^(g), —OS(═O)₁₋₂R^(g),—S(═O)₁₋₂OR^(g), —NR^(g)S(═O)₁₋₂NR^(g)R^(h), ═NSO₂R^(g), ═NOR^(g),—S(═O)₁₋₂NR^(g)R^(h), —SF₅, —SCF₃ or —OCF₃. In certain embodiments,“substituted” also means any of the above groups in which one or more(e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced with—C(═O)R^(g), —C(═O)OR^(g), —C(═O)NR^(g)R^(h), —CH₂SO₂R^(g), or—CH₂SO₂NR^(g)R^(h). In the foregoing, R^(g) and R^(h) are the same ordifferent and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy,thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl. Incertain embodiments, “substituted” also means any of the above groups inwhich one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms arereplaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo,thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl, or two of R^(g)and R^(h) and R^(i) are taken together with the atoms to which they areattached to form a heterocyclyl ring optionally substituted with oxo,halo or alkyl optionally substituted with oxo, halo, amino, hydroxyl, oralkoxy.

Polymers or similar indefinite structures arrived at by definingsubstituents with further substituents appended ad infinitum (e.g., asubstituted aryl having a substituted alkyl which is itself substitutedwith a substituted aryl group, which is further substituted by asubstituted heteroalkyl group, etc.) are not intended for inclusionherein. Unless otherwise noted, the maximum number of serialsubstitutions in compounds described herein is three. For example,serial substitutions of substituted aryl groups with two othersubstituted aryl groups are limited to ((substituted aryl)substitutedaryl) substituted aryl. Similarly, the above definitions are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluorines or heteroaryl groups having two adjacentoxygen ring atoms). Such impermissible substitution patterns are wellknown to the skilled artisan. When used to modify a chemical group, theterm “substituted” may describe other chemical groups defined herein.

In certain embodiments, as used herein, the phrase “one or more” refersto one to five. In certain embodiments, as used herein, the phrase “oneor more” refers to one to four. In certain embodiments, as used herein,the phrase “one or more” refers to one to three.

Any compound or structure given herein, is intended to representunlabeled forms as well as isotopically labeled forms (isotopologues) ofthe compounds. These forms of compounds may also be referred to as andinclude “isotopically enriched analogs.” Isotopically labeled compoundshave structures depicted herein, except that one or more atoms arereplaced by an atom having a selected atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, chlorine and iodine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵Irespectively. Various isotopically labeled compounds of the presentdisclosure, for example those into which radioactive isotopes such as³H, ¹³C and ¹⁴C are incorporated. Such isotopically labelled compoundsmay be useful in metabolic studies, reaction kinetic studies, detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays or in radioactive treatment ofpatients.

The term “isotopically enriched analogs” includes “deuterated analogs”of compounds described herein in which one or more hydrogens is/arereplaced by deuterium, such as a hydrogen on a carbon atom. Suchcompounds exhibit increased resistance to metabolism and are thus usefulfor increasing the half-life of any compound when administered to amammal, particularly a human. See, for example, Foster, “DeuteriumIsotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well knownin the art, for example by employing starting materials in which one ormore hydrogens have been replaced by deuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F, ³H, ¹¹C labeled compoundmay be useful for PET or SPECT or other imaging studies. Isotopicallylabeled compounds of this disclosure and prodrugs thereof can generallybe prepared by carrying out the procedures disclosed in the schemes orin the examples and preparations described below by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent. It is understood that deuterium in this context isregarded as a substituent in a compound described herein.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium. Further, in some embodiments, the correspondingdeuterated analog is provided.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Provided also are a pharmaceutically acceptable salt, isotopicallyenriched analog, deuterated analog, isomer (such as a stereoisomer),mixture of isomers (such as a mixture of stereoisomers), prodrug, andmetabolite of the compounds described herein.

“Pharmaceutically acceptable” or “physiologically acceptable” refer tocompounds, salts, compositions, dosage forms and other materials whichare useful in preparing a pharmaceutical composition that is suitablefor veterinary or human pharmaceutical use.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound and which are not biologically or otherwise undesirable.“Pharmaceutically acceptable salts” or “physiologically acceptablesalts” include, for example, salts with inorganic acids and salts withan organic acid. In addition, if the compounds described herein areobtained as an acid addition salt, the free base can be obtained bybasifying a solution of the acid salt. Conversely, if the product is afree base, an addition salt, particularly a pharmaceutically acceptableaddition salt, may be produced by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts from basecompounds. Those skilled in the art will recognize various syntheticmethodologies that may be used to prepare nontoxic pharmaceuticallyacceptable addition salts. Pharmaceutically acceptable acid additionsalts may be prepared from inorganic and organic acids. Salts derivedfrom inorganic acids include, e.g., hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid and the like. Salts derivedfrom organic acids include, e.g., acetic acid, propionic acid, gluconicacid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonicacid, succinic acid, maleic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid and thelike. Likewise, pharmaceutically acceptable base addition salts can beprepared from inorganic and organic bases. Salts derived from inorganicbases include, by way of example only, sodium, potassium, lithium,aluminum, ammonium, calcium and magnesium salts. Salts derived fromorganic bases include, but are not limited to, salts of primary,secondary and tertiary amines, such as alkyl amines (i.e., NH₂(alkyl)),dialkyl amines (i.e., HN(alkyl)₂), trialkyl amines (i.e., N(alkyl)₃),substituted alkyl amines (i.e., NH₂(substituted alkyl)), di(substitutedalkyl) amines (i.e., HN(substituted alkyl)₂), tri(substituted alkyl)amines (i.e., N(substituted alkyl)₃), alkenyl amines (i.e.,NH₂(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)₂), trialkenyl amines(i.e., N(alkenyl)₃), substituted alkenyl amines (i.e., NH₂(substitutedalkenyl)), di(substituted alkenyl) amines (i.e., HN(substitutedalkenyl)₂), tri(substituted alkenyl) amines (i.e., N(substitutedalkenyl)₃, mono-, di- or tri-cycloalkyl amines (i.e., NH₂(cycloalkyl),HN(cycloalkyl)₂, N(cycloalkyl)₃), mono-, di- or tri-arylamines (i.e.,NH₂(aryl), HN(aryl)₂, N(aryl)₃) or mixed amines, etc. Specific examplesof suitable amines include, by way of example only, isopropylamine,trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine,morpholine, N-ethylpiperidine and the like.

The term “hydrate” refers to the complex formed by the combining of acompound described herein and water.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the disclosure. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid andethanolamine.

Some of the compounds exist as tautomers. Tautomers are in equilibriumwith one another. For example, amide containing compounds may exist inequilibrium with imidic acid tautomers. Regardless of which tautomer isshown and regardless of the nature of the equilibrium among tautomers,the compounds are understood by one of ordinary skill in the art tocomprise both amide and imidic acid tautomers. Thus, the amidecontaining compounds are understood to include their imidic acidtautomers. Likewise, the imidic acid containing compounds are understoodto include their amide tautomers.

The compounds of the invention, or their pharmaceutically acceptablesalts include an asymmetric center and may thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh performance liquid chromatography (HPLC). When the compoundsdescribed herein contain olefinic double bonds or other centres ofgeometric asymmetry, and unless specified otherwise, it is intended thatthe compounds include both E and Z geometric isomers.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers,”which refers to two stereoisomers whose molecules are nonsuperimposablemirror images of one another.

“Diastereomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

Relative centers of the compounds as depicted herein are indicatedgraphically using the “thick bond” style (bold or parallel lines) andabsolute stereochemistry is depicted using wedge bonds (bold or parallellines).

“Prodrugs” means any compound which releases an active parent drugaccording to a structure described herein in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of a compound describedherein are prepared by modifying functional groups present in thecompound described herein in such a way that the modifications may becleaved in vivo to release the parent compound. Prodrugs may be preparedby modifying functional groups present in the compounds in such a waythat the modifications are cleaved, either in routine manipulation or invivo, to the parent compounds. Prodrugs include compounds describedherein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in acompound described herein is bonded to any group that may be cleaved invivo to regenerate the free hydroxy, amino, or sulfhydryl group,respectively. Examples of prodrugs include, but are not limited toesters (e.g., acetate, formate and benzoate derivatives), amides,guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyfunctional groups in compounds described herein and the like.Preparation, selection and use of prodrugs is discussed in T. Higuchiand V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of theA.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard,Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. EdwardB. Roche, American Pharmaceutical Association and Pergamon Press, 1987,each of which are hereby incorporated by reference in their entirety.

The term, “metabolite,” as used herein refers to a resulting productformed when a compound disclosed herein is metabolized. As used herein,the term “metabolized” refers to the sum of processes (including but notlimited to hydrolysis reactions and reactions catalyzed by enzymes) bywhich a particular substance, such as a compound disclosed herein, ischanged by an organism. For example, an aldehyde moiety (—C(O)H) may bereduced in vivo to a —CH₂OH moiety.

Use of the word “inhibitor,” “inhibit” or “inhibition,” herein refers toactivity of a compound of Formula I or a pharmaceutically acceptablesalt on ferroportin, unless specified otherwise. By “inhibit” herein ismeant to decrease the activity of ferroportin, as compared to theactivity of ferroportin in the absence of the compound. In someembodiments, the term “inhibit” means a decrease in ferroportin activityof at least about 5%, at least about 10%, at least about 20%, at leastabout 25%, at least about 50%, at least about 60%, at least about 70%,at least about 80%, at least about 90%, or at least about 95%. In otherembodiments, inhibit means a decrease in ferroportin activity of about5% to about 25%, about 25% to about 50%, about 50% to about 75%, orabout 75% to 100%. In some embodiments, inhibit means a decrease inferroportin activity of about 95% to 100%, e.g., a decrease in activityof 95%, 96%, 97%, 98%, 99%, or 100%. Such decreases can be measuredusing a variety of techniques that would be recognizable by one of skillin the art, including in vitro assays.

As used herein, the term “ferroportin inhibitor” and the like refers toa compound that reduces, inhibits, or otherwise diminishes one or moreof the biological activities of ferroportin, for instance by inducinginternalization of ferroportin. The activity could decrease by astatistically significant amount including, for example, a decrease ofat least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, 80%, 85%, 95% or 100% of the activity of ferroportincompared to an appropriate control.

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing effectof another medication, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human.

The term “therapeutically effective amount” or “effective amount” of acompound described herein or a pharmaceutically acceptable salt,tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuteratedanalog thereof means an amount sufficient to effect treatment whenadministered to a subject, to provide a therapeutic benefit such asamelioration of symptoms or slowing of disease progression. For example,a therapeutically effective amount may be an amount sufficient todecrease a symptom of a sickle cell disease. The therapeuticallyeffective amount may vary depending on the subject, and disease orcondition being treated, the weight and age of the subject, the severityof the disease or condition, and the manner of administering, which canreadily be determined by one of ordinary skill in the art.

When any variable or substituent occurs more than one time in anystructure or formulae, its definition in each occurrence is independentof its definition at every other occurrence. Combinations ofsubstituents and/or variables are permissible only if such combinationsresult in chemically stable compounds. It is understood thatsubstituents and substitution patterns on the compounds described hereincan be selected by one of ordinary skill in the art to provide compoundsthat are chemically stable and that can be readily synthesized bytechniques known in the art as well as those methods set forth herein.

Additional definitions may also be provided below as appropriate.

II. Compounds

In certain embodiments, the subject matter described herein is directedto compounds of Formula I′:

or a pharmaceutically acceptable salt thereof; wherein,

Z is N or CH;

Ring B is

wherein

indicates the point of attachment to the remainder of the molecule;

-   -   R⁶, in each instance, is selected from the group consisting of        halogen, hydroxy, C₁-C₃ alkoxy, C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃        alkyl, hydroxy-C₁-C₁₀ alkoxy, hydroxy-C₁-C₁₀-alkyl, cyano,        —NR^(G)R^(H), halo-C₁-C₃ alkoxy, —O—(C₁-C₆ alkyl)-R^(bb),        —O—R^(bb), —(C₁-C₆ alkyl)-NR^(GI)R^(HI), —S—C₁-C₃ alkyl,        —S—C₁-C₃ alkyl-NR^(G1)R^(H1), halo-C₁-C₃ alkyl,        —O—R^(cc)—O—R^(dd), 5- to 7-membered monocyclic heteroaryl, and        C₃-C₆ cycloalkyl; wherein,    -   the alkyl moiety in hydroxy-C₁-C₁₀ alkoxy or —O—(C₁-C₆        alkyl)-R^(bb) is optionally substituted with cyano, hydroxy,        hydroxy-C₁-C₃-alkyl, halogen, or C₁-C₃ alkoxy;        -   R^(bb) is 4- to 7-membered monocyclic or bridged            heterocyclyl, C₃-C₇ cycloalkyl, 5- or 6-membered monocyclic            heteroaryl, —SO₂—C₁-C₃ alkyl, —S—C₁-C₃ alkyl,            —C(O)NR^(G1)R^(H1), or —NR^(G)R^(H);        -   R^(cc) is C₁-C₃ alkyl; and        -   R^(dd) is C₁-C₃ alkyl or a 6-membered heteroaryl;            -   wherein, said cycloalkyl, heterocyclyl, or heteroaryl of                R⁶, R^(bb), or R^(dd) is optionally substituted with one                or two substituents, each independently selected from                the group consisting of hydroxy, halogen, halo-C₁-C₃                alkyl, oxo, C₁-C₃ alkoxy, and C₁-C₃ alkyl;        -   R^(G1) and R^(H1) are each independently hydrogen or C₁-C₃            alkyl;    -   and,        -   R^(G) and R^(H) are each independently hydrogen,            —C(O)R^(Ga), or optionally deuterated C₁-C₃ alkyl; wherein,            -   R^(Ga) is C₁-C₃ alkyl or hydrogen;

or,

-   -   two R⁶ groups, taken together with the atom to which each is        attached, form a 5- or 6-membered monocyclic heterocyclyl fused        with Ring B, a C₄-C₇ cycloalkyl fused with Ring B, a phenyl        fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl        fused with Ring B; wherein,        -   said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused            with ring B is optionally substituted with one or two            substituents, each independently selected from the group            consisting of C₁-C₃ alkoxy, hydroxy, hydroxy-C₁-C₃-alkyl,            C₁-C₃ alkyl, C₃-C₇ cycloalkyl, and 5- or 6-membered            monocyclic heterocyclyl;    -   n is 0, 1, 2, or 3;    -   Y¹, Y², Y³, and Y⁴ are each independently selected from the        group consisting of CH, N, NH, O, S, SH, S—R⁶, N—R⁶, and C—R⁶,        provided that 1 or 2 of Y¹, Y², Y³, and Y⁴ can be N, N—R⁶, NH,        O, SH or S—R⁶;    -   f is 0 or 1;

p is 1 or 2;

R^(x), in each instance, is halogen, C₁-C₆ alkyl, C₁-C₃ alkoxy, hydroxy,oxo, or cyano;

m is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, optionallydeuterated C₁-C₃ alkyl, hydroxy-C₁-C₃ alkyl, halo-C₁-C₃ alkyl,cyclopropyl, and phenyl;

R⁴ is selected from the group consisting of:

-   -   i. (5- to 10-membered monocyclic or fused bicyclic        heteroaryl)-C₁-C₃ alkyl, or (6- or 7-membered monocyclic        heterocyclyl)-C₁-C₃ alkyl; wherein,        -   said heteroaryl or heterocyclyl is optionally substituted            with one or two substituents, each independently selected            from the group consisting of C₆-C₁₀ monocyclic or fused            bicyclic aryl, C₃-C₇ cycloalkyl, 5- or 6-membered            heteroaryl, —(C₁-C₃ alkyl)-T, and 5- to 7-membered            monocyclic heterocyclyl;            -   T is selected from the group consisting of C₆-C₁₀                monocyclic or fused bicyclic aryl, C₃-C₇ cycloalkyl, 5-                or 6-membered heteroaryl, and 5- to 7-membered                monocyclic heterocyclyl; and,                -   wherein T or said aryl, cycloalkyl, heteroaryl, or                    heterocyclyl substituent of R⁴ is optionally                    substituted with one or two substituents, each                    individually selected from the group consisting of                    C₁-C₃ alkyl, halogen, and hydroxy; and        -   when p is 1, C₁-C₃ alkyl in the (5- to 10-membered            monocyclic or fused bicyclic heteroaryl)-C₁-C₃ alkyl is            linear;

and,

-   -   ii.

-   -   wherein,        -   R^(4a) and R^(4g) are each independently selected from the            group consisting of hydrogen, C₁-C₁₀ alkyl, hydroxy-C₁-C₆            alkyl, halo-C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₆ alkyl, —C₁-C₆            alkyl-NR^(J1)R^(J2), C₃-C₇ cycloalkyl, 4- to 10-membered            monocyclic, fused bicyclic, bridged bicyclic, or spiro            heterocyclyl, C₆-C₁₀ monocyclic or fused bicyclic aryl, 5-            to 10-membered monocyclic or fused bicyclic heteroaryl,            (C₆-C₁₀ monocyclic or fused bicyclic aryl)-C₁-C₃ alkyl, and            (5- to 10-membered monocyclic or fused bicyclic            heteroaryl)-C₁-C₃ alkyl;            -   R^(J1) and R^(J2) are independently hydrogen or C₁-C₃                alkyl;            -   wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl,                aryl-alkyl, or heteroaryl-alkyl of R^(4a) or R^(4g) is                optionally substituted with one, two, or three                substituents, each independently selected from the group                consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl,                hydroxy, C₁-C₃ alkoxy, halo-C₁-C₃ alkoxy, oxo, C₃-C₇                cycloalkyl, and 5- to 10-membered monocyclic, fused                bicyclic, or spiro heterocyclyl;        -   R^(4b) is hydrogen or C₁-C₆ alkyl; or        -   R^(4a) and R^(4b) taken together with the atom to which each            is attached form a 5- to 10-membered monocyclic, fused            bicyclic, or bridged bicyclic heterocyclyl, optionally            substituted with one or two substituents, each independently            selected from the group consisting of halogen, C₁-C₆ alkyl,            halo-C₁-C₃ alkyl, hydroxy, and C₁-C₃ alkoxy; or        -   R^(4b) and R^(4c) taken together with the atom to which each            is attached form a 5- to 7-membered monocyclic heterocyclyl            optionally substituted with one, two, or three substituents,            each independently selected from the group consisting of            hydroxy, halogen, and C₁-C₃ alkyl; or        -   R^(4c) and R^(4d) are each independently selected from the            group consisting of hydrogen, C₁-C₃ alkoxy, hydroxy, C₁-C₃            alkyl-thio-C₁-C₃ alkyl, hydroxy-C₁-C₆ alkyl, C₁-C₆            alkoxy-C₁-C₃ alkyl, C₃-C₇ cycloalkyl, and C₁-C₃ alkyl; or        -   R^(4c) and R^(4d) taken together with the atom to which each            is attached form a C₃-C₇ cycloalkyl;

or, when p is 1,

-   -   R³ and R⁴ taken together with the nitrogen atom to which each is        attached can form a:        -   i. 7-membered fused bicyclic heterocyclyl, 7-membered            bridged bicyclic heterocyclyl, or 7-membered monocyclic            heterocyclyl containing one or two heteroatoms;            -   wherein when said 7-membered monocyclic heterocyclyl                contains one heteroatom, said heterocyclyl is optionally                substituted with one, two, or three substituents, each                independently selected from the group consisting of oxo,                halogen, hydroxy, C₁-C₃ alkoxy, cyano, and C₁-C₃ alkyl;                and,            -   when said 7-membered monocyclic heterocyclyl contains                two heteroatoms, said heteroatoms are each independently                N or O, and said heterocyclyl is optionally substituted                with one, two, or three substituents, each independently                selected from the group consisting of C₁-C₃ alkyl,                cyano, oxo, halogen, halo-C₁-C₃ alkyl, and C₆-C₁₀                monocyclic or fused bicyclic aryl; and                -   wherein said aryl is optionally substituted with one                    or two substituents, each individually selected from                    the group consisting of C₁-C₃ alkoxy, hydroxy,                    halogen, and C₁-C₃ alkyl;        -   ii. 4- or 6-membered monocyclic heterocyclyl containing one            heteroatom;            -   wherein said 4-membered monocyclic heterocyclyl is                optionally substituted with one or two substituents,                each independently selected from the group consisting of                halogen, C₁-C₃ alkoxy, oxo, and                —(CH₂)_(s)C(═O)NR^(k)R^(l); wherein,                -   s is 0, 1, 2, or 3;                -   R^(k) is hydrogen or C₁-C₃ alkyl; and                -   R^(l) is selected from the group consisting of                    hydrogen, hydroxy, C₁-C₃ alkyl, C₃-C₇ cycloalkyl,                    and C₆-C₁₀ monocyclic or fused bicyclic aryl;            -   wherein said 6-membered monocyclic heterocyclyl is                optionally substituted with one or two substituents,                each independently selected from the group consisting of                C₁-C₃ alkoxy, oxo, halogen, cyano, and —NR^(q)R^(w);                wherein,                -   R^(q) is hydrogen or C₁-C₃ alkyl; and                -   R^(w) is C₆-C₁₀ monocyclic or fused bicyclic aryl or                    C₃-C₇ cycloalkyl, wherein said aryl or cycloalkyl is                    optionally substituted with one or two substituents,                    each independently selected from the group                    consisting of halogen, C₁-C₃ alkyl, hydroxy, and                    C₁-C₃ alkoxy;    -   or,        -   iii. 8-, 9-, 10- or 11-membered fused bicyclic heterocyclyl,            or 12-membered bicyclic bridged and fused heterocyclyl,            wherein said 8-, 9-, or 11-membered heterocyclyl contains            one heteroatom and said 10- or 12-membered heterocyclyl            contains one or two heteroatoms; and wherein said 10-, 11-,            or 12-membered heterocyclyl is optionally substituted with            one, two, or three substituents, each independently selected            from the group consisting of halogen, C₁-C₃ alkyl, C₁-C₃            alkoxy, and hydroxy;

or, when p is 2,

-   -   R³ and R⁴ taken together with the nitrogen atom to which each is        attached can form a:        -   i. 6-membered monocyclic heterocyclyl containing one            heteroatom, optionally substituted with one or two            substituents, each independently selected from the group            consisting of halogen, hydroxy-(C₁-C₆ alkyl), hydroxy, oxo,            and C₁-C₃ alkoxy; or        -   ii. 4- or 7-membered monocyclic heterocyclyl containing one            or two heteroatoms, or 7-, 8-, 9-, 10-, or 11-membered            bridged bicyclic, fused bicyclic, or spiro heterocyclyl            containing one, two, or three heteroatoms, optionally            substituted with one or two substituents, each independently            selected from the group consisting of halogen, oxo,    -   cyano, C₁-C₃ alkyl, hydroxy, —NR^(G)R^(H), and        —(CH₂)_(s)C(═O)NR^(k)R^(l);

provided that when the structure of Formula (I) is

* is

and ** is

; or

* is

and ** is

;

and,

wherein the compound of Formula (I) is not:

-   N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine;-   4-(piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;-   4-(azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;-   1-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one;    or-   2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane;    or a salt thereof.

In certain embodiments, the subject matter described herein is directedto compounds of Formula I′:

or a pharmaceutically acceptable salt thereof; wherein,

Z is N or CH;

Ring B is

wherein

indicates the point of attachment to the remainder of the molecule;

-   -   R⁶, in each instance, is selected from the group consisting of        halogen, hydroxy, C₁-C₃ alkoxy, C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃        alkyl, hydroxy-C₁-C₆ alkoxy, hydroxy-C₁-C₃-alkyl, cyano,        —NR^(G)R^(H), halo-C₁-C₃ alkoxy, —O—(CH₂)_(u)—R^(bb), halo-C₁-C₃        alkyl, —O—R^(cc)—O—R^(dd), 5- to 7-membered monocyclic        heteroaryl, and C₃-C₆ cycloalkyl; wherein,        -   u is an integer from 0 to 6;        -   R^(bb) is 4- to 7-membered monocyclic heterocyclyl, C₃-C₇            cycloalkyl, or —NR^(G)R^(H);        -   R^(cc) and R^(dd) are each independently C₁-C₃ alkyl;            -   wherein, said cycloalkyl, heterocyclyl, or heteroaryl is                optionally substituted with one or two substituents,                each independently selected from the group consisting of                hydroxy, C₁-C₃ alkoxy, and C₁-C₃ alkyl;    -   and,        -   R^(G) and R^(H) are each independently hydrogen,            —C(O)R^(Ga), or C₁-C₃ alkyl; wherein,            -   R^(Ga) is C₁-C₃ alkyl or hydrogen;

or,

-   -   two R⁶ groups, taken together with the atom to which each is        attached, form a 5- or 6-membered monocyclic heterocyclyl fused        with Ring B, a C₄-C₇ cycloalkyl fused with Ring B, a phenyl        fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl        fused with Ring B; wherein,        -   said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused            with ring B is optionally substituted with one or two            substituents, each independently selected from the group            consisting of C₁-C₃ alkoxy, hydroxy, hydroxy-C₁-C₃-alkyl,            C₁-C₃ alkyl, C₃-C₇ cycloalkyl, and 5- or 6-membered            monocyclic heterocyclyl;    -   n is 0, 1, 2, or 3;    -   Y¹, Y², Y³, and Y⁴ are each independently selected from the        group consisting of CH, N, NH, O, S, SH, S—R⁶, N—R⁶, and C—R⁶,        provided that 1 or 2 of Y¹, Y², Y³, and Y⁴ can be N, N—R⁶, NH,        O, SH or S—R⁶;    -   f is 0 or 1;

p is 1 or 2;

R^(x), in each instance, is halogen, C₁-C₆ alkyl, C₁-C₃ alkoxy, hydroxy,or cyano;

m is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, C₁-C₃ alkyl,hydroxy-C₁-C₃ alkyl, cyclopropyl, and phenyl;

R⁴ is selected from the group consisting of:

-   -   i. (5- to 10-membered monocyclic or fused bicyclic        heteroaryl)-C₁-C₃ alkyl branched or linear, or (6- or 7-membered        monocyclic heterocyclyl)-C₁-C₃ alkyl branched or linear;        wherein,        -   said heteroaryl or heterocyclyl is optionally substituted            with one or two substituents, each independently selected            from the group consisting of C₆-C₁₀ monocyclic or fused            bicyclic aryl, C₃-C₇ cycloalkyl, 5- or 6-membered            heteroaryl, and 5- to 7-membered monocyclic heterocyclyl,            and wherein said aryl, cycloalkyl, heteroaryl, or            heterocyclyl is optionally substituted with one or two            substituents, each individually selected from the group            consisting of C₁-C₃ alkyl, halogen, and hydroxy; and,        -   when p is 1, C₁-C₃ alkyl in the (5- to 10-membered            monocyclic or fused bicyclic heteroaryl)-C₁-C₃ alkyl is            linear;

and,

-   -   ii.

-   -   wherein,        -   R^(4a) and R^(4g) are each independently selected from the            group consisting of hydrogen, C₁-C₆ alkyl, hydroxy-C₁-C₆            alkyl, C₁-C₃ alkoxy-C₁-C₆ alkyl, C₃-C₇ cycloalkyl, 5- to            10-membered monocyclic, fused bicyclic, bridged bicyclic, or            spiro heterocyclyl, C₆-C₁₀ monocyclic or fused bicyclic            aryl, 5- to 10-membered monocyclic or fused bicyclic            heteroaryl, (C₆-C₁₀ monocyclic or fused bicyclic aryl)-C₁-C₃            alkyl, and (5- to 10-membered monocyclic or fused bicyclic            heteroaryl)-C₁-C₃ alkyl;            -   wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl,                aryl-alkyl, or heteroaryl-alkyl of R^(4a) or R^(4g) is                optionally substituted with one, two, or three                substituents, each independently selected from the group                consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl,                hydroxy, C₁-C₃ alkoxy, halo-C₁-C₃ alkoxy, oxo, C₃-C₇                cycloalkyl, and 5- to 10-membered monocyclic, fused                bicyclic, or spiro heterocyclyl;        -   R^(4b) is hydrogen or C₁-C₆ alkyl; or        -   R^(4a) and R^(4b) taken together with the atom to which each            is attached form a 5- to 10-membered monocyclic, fused            bicyclic, or bridged bicyclic heterocyclyl, optionally            substituted with one or two substituents, each independently            selected from the group consisting of halogen, C₁-C₆ alkyl,            halo-C₁-C₃ alkyl, hydroxy, and C₁-C₃ alkoxy; or        -   R^(4b) and R^(4c) taken together with the atom to which each            is attached form a 5- to 7-membered monocyclic heterocyclyl            optionally substituted with one, two, or three substituents,            each independently selected from the group consisting of            hydroxy, halogen, and C₁-C₃ alkyl; or        -   R^(4c) and R^(4d) are each independently selected from the            group consisting of hydrogen, C₁-C₃ alkoxy, hydroxy, C₁-C₃            alkyl-thio-C₁-C₃ alkyl, hydroxy-C₁-C₆ alkyl, C₁-C₆            alkoxy-C₁-C₃ alkyl, C₃-C₇ cycloalkyl, and C₁-C₃ alkyl; or        -   R^(4c) and R^(4d) taken together with the atom to which each            is attached form a C₃-C₇ cycloalkyl;

or, when p is 1,

-   -   R³ and R⁴ taken together with the nitrogen atom to which each is        attached can form a:        -   i. 7-membered fused bicyclic heterocyclyl, 7-membered            bridged bicyclic heterocyclyl, or 7-membered monocyclic            heterocyclyl containing one or two heteroatoms;            -   wherein when said 7-membered monocyclic heterocyclyl                contains one heteroatom, said heterocyclyl is optionally                substituted with one, two, or three substituents, each                independently selected from the group consisting of oxo,                halogen, hydroxy, C₁-C₃ alkoxy, cyano, and C₁-C₃ alkyl;                and,            -   when said 7-membered monocyclic heterocyclyl contains                two heteroatoms, said heteroatoms are each independently                N or O, and said heterocyclyl is optionally substituted                with one, two, or three substituents, each independently                selected from the group consisting of C₁-C₃ alkyl,                cyano, oxo, halogen, halo-C₁-C₃ alkyl, and C₆-C₁₀                monocyclic or fused bicyclic aryl; and                -   wherein said aryl is optionally substituted with one                    or two substituents, each individually selected from                    the group consisting of C₁-C₃ alkoxy, hydroxy,                    halogen, and C₁-C₃ alkyl;        -   ii. 4- or 6-membered monocyclic heterocyclyl containing one            heteroatom;            -   wherein said 4-membered monocyclic heterocyclyl is                optionally substituted with one or two substituents,                each independently selected from the group consisting of                halogen, C₁-C₃ alkoxy, oxo, and                —(CH₂)_(s)C(═O)NR^(k)R^(l); wherein,                -   s is 0, 1, 2, or 3;                -   R^(k) is hydrogen or C₁-C₃ alkyl; and                -   R^(l) is selected from the group consisting of                    hydrogen, hydroxy, C₁-C₃ alkyl, C₃-C₇ cycloalkyl,                    and C₆-C₁₀ monocyclic or fused bicyclic aryl;            -   wherein said 6-membered monocyclic heterocyclyl is                optionally substituted with one or two substituents,                each independently selected from the group consisting of                C₁-C₃ alkoxy, oxo, halogen, cyano, and —NR^(q)R^(w);                wherein,                -   R^(q) is hydrogen or C₁-C₃ alkyl; and                -   R^(w) is C₆-C₁₀ monocyclic or fused bicyclic aryl or                    C₃-C₇ cycloalkyl, wherein said aryl or cycloalkyl is                    optionally substituted with one or two substituents,                    each independently selected from the group                    consisting of halogen, C₁-C₃ alkyl, hydroxy, and                    C₁-C₃ alkoxy;    -   or,        -   iii. 8-, 9-, 10- or 11-membered fused bicyclic heterocyclyl,            or 12-membered bicyclic bridged and fused heterocyclyl,            wherein said 8-, 9-, or 11-membered heterocyclyl contains            one heteroatom and said 10- or 12-membered heterocyclyl            contains one or two heteroatoms; and wherein said 10-, 11-,            or 12-membered heterocyclyl is optionally substituted with            one, two, or three substituents, each independently selected            from the group consisting of halogen, C₁-C₃ alkyl, C₁-C₃            alkoxy, and hydroxy;

or, when p is 2,

-   -   R³ and R⁴ taken together with the nitrogen atom to which each is        attached can form a:        -   i. 6-membered monocyclic heterocyclyl containing one            heteroatom, optionally substituted with one or two            substituents, each independently selected from the group            consisting of halogen, hydroxy-(C₁-C₆ alkyl), hydroxy, oxo,            and C₁-C₃ alkoxy; or        -   ii. 4- or 7-membered monocyclic heterocyclyl containing one            or two heteroatoms, or 7-, 8-, 9-, 10-, or 11-membered            bridged bicyclic, fused bicyclic, or spiro heterocyclyl            containing one, two, or three heteroatoms, optionally            substituted with one or two substituents, each independently            selected from the group consisting of halogen, oxo, cyano,            C₁-C₃ alkyl, hydroxy, —NR^(G)R^(H), and            —(CH₂)_(s)C(═O)NR^(k)R^(l);

provided that when the structure of Formula (I) is

* is

and ** is

; or

* is

and ** is

;

and,

wherein the compound of Formula (I) is not:

-   N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine;-   4-(piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;-   4-(azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;-   1-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one;    or-   2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane;    or a salt thereof.

In certain embodiments, the subject matter described herein is directedto compounds of Formula I:

wherein,

Z is N or CH;

R⁶, in each instance, is selected from the group consisting of halogen,hydroxy, C₁-C₃ alkoxy, C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃ alkyl,hydroxy-C₁-C₆ alkoxy, hydroxy-C₁-C₃-alkyl, cyano, C₃-C₇ cycloalkyl-C₁-C₃alkoxy, NR^(G)R^(H), halo-C₁-C₃ alkoxy, and C₃-C₆ cycloalkyl;

-   -   wherein R^(G) and R^(H) are each independently hydrogen or C₁-C₃        alkyl;

or, wherein two R⁶ groups, taken together with the atom to which each isattached, form a 5- or 6-membered heterocyclyl, C₃-C₇ cycloalkyl, C₆-C₁₀aryl, or 5- to 10-membered heteroaryl;

n is 0, 1, 2, or 3;

Y¹, Y², Y³, and Y⁴ are each independently selected from the groupconsisting of CH, N, NH, O, S, and C (when R⁶ is attached thereto),provided that 1 or 2 of Y¹, Y², Y³, and Y⁴ can be N, NH, O, or S;

f is 0 or 1;

p is 1 or 2;

R^(x), in each instance, is halogen, C₁-C₆ alkyl, C₁-C₃ alkoxy, hydroxy,or cyano;

m is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, C₁-C₃ alkyl,hydroxy-C₁-C₃-alkyl, cyclopropyl, and phenyl;

R⁴ is selected from the group consisting of:

i. (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-C₁-C₃alkyl branched or linear, or (6- or 7-membered monocyclicheterocyclyl)-C₁-C₃ alkyl branched or linear;

wherein,

-   -   when p is 1, C₁-C₃ alkyl in (5- to 10-membered monocyclic or        bicyclic fused heteroaryl)-C₁-C₃ alkyl is linear;        and,

ii.

wherein,

-   -   R^(4a) and R^(4g) are each independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, hydroxy-C₁-C₆ alkyl, C₁-C₃        alkoxy-C₁-C₆ alkyl, C₃-C₇ cycloalkyl, 5- to 10-membered        monocyclic, bicyclic fused, or spiro heterocyclyl, C₆-C₁₀ aryl,        5- to 10-membered monocyclic or bicyclic fused heteroaryl,        (C₆-C₁₀ aryl)-C₁-C₃ alkyl, and (5- to 10-membered monocyclic        heteroaryl)-C₁-C₃ alkyl;    -   wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl,        arylalkyl, or heteroaryl-alkyl of R^(4a) or R^(4g) is optionally        substituted with one, two, or three substituents, each        independently selected from the group consisting of halogen,        C₁-C₆ alkyl, haloalkyl, hydroxy, C₁-C₃ alkoxy, oxo, C₃-C₇        cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or        spiro heterocyclyl;    -   R^(4b) is hydrogen or C₁-C₆ alkyl;    -   or, R^(4a) and R^(4b) taken together with the atom to which each        is attached form a 5- to 7-membered heterocyclyl;    -   or, R^(4b) and R^(4c) taken together with the atom to which each        is attached form a 5- to 7-membered heterocyclyl optionally        substituted with one, two, or three substituents, each        independently selected from the group consisting of hydroxy,        halo, and C₁-C₃ alkyl;    -   R^(4c) and R^(4d) are each independently selected from the group        consisting of hydrogen, C₁-C₃ alkoxy, hydroxy, C₁-C₃        alkyl-thio-C₁-C₃ alkyl, hydroxy-C₁-C₆ alkyl, C₁-C₆ alkoxy-C₁-C₃        alkyl, C₃-C₇ cycloalkyl, and C₁-C₃ alkyl;    -   or, R^(4c) and R^(4d) taken together with the atom to which each        is attached form a C₃-C₇ cycloalkyl;

or, when p is 1,

R³ and R⁴ taken together with the nitrogen atom to which each isattached can form a:

i. 7-membered bicyclic fused heterocyclyl, 7-membered bridgedheterocyclyl, or 7-membered monocyclic heterocyclyl containing one ortwo heteroatoms;

-   -   wherein when said 7-membered monocyclic heterocyclyl contains        one heteroatom, said heterocyclyl is optionally substituted with        one, two, or three substituents, each independently selected        from the group consisting of oxo, halogen, hydroxy, C₁-C₃        alkoxy, cyano, and C₁-C₃ alkyl; and    -   when said 7-membered monocyclic heterocyclyl contains two        heteroatoms, said heteroatoms are each independently N or O, and        said heterocyclyl is optionally substituted with one, two, or        three substituents, each independently selected from the group        consisting of C₁-C₃ alkyl, cyano, oxo, halogen, haloalkyl, and        C₆-C₁₀ aryl; and wherein said aryl is optionally substituted        with one or two substituents, each individually selected from        the group consisting of C₁-C₃ alkoxy, hydroxy, halogen, and        C₁-C₃ alkyl;

ii. 4- or 6-membered monocyclic heterocyclyl containing one heteroatom;

-   -   wherein said 4-membered monocyclic heterocyclyl is optionally        substituted with one or two substituents, each independently        selected from the group consisting of halogen, C₁-C₃ alkoxy,        oxo, and —(CH₂)_(s)C(═O)NR^(k)R^(l);        -   wherein s is 0, 1, 2, or 3;        -   R^(k) is hydrogen or C₁-C₃ alkyl; and        -   R^(l) is selected from the group consisting of hydrogen,            hydroxy, C₁-C₃ alkyl, C₃-C₇ cycloalkyl, and C₆-C₁₀ aryl;    -   wherein said 6-membered monocyclic heterocyclyl is optionally        substituted with one or two substituents, each independently        selected from the group consisting of C₁-C₃ alkoxy, oxo,        halogen, cyano, and NR^(q)R^(w);    -   wherein R^(q) is hydrogen or C₁-C₃ alkyl and R^(w) is C₆-C₁₀        aryl or C₃-C₇ cycloalkyl, and wherein said aryl or cycloalkyl is        optionally substituted with one or two substituents, each        independently selected from the group consisting of halogen,        C₁-C₃ alkyl, hydroxy, and C₁-C₃ alkoxy;

iii. 8-, 9-, 10- or 11-membered bicyclic fused heterocyclyl, or12-membered bicyclic bridged, fused heterocyclyl, wherein said 8-, 9-,or 11-membered heterocyclyl contains one heteroatom and said 10- or12-membered heterocyclyl contains one or two heteroatoms; and whereinsaid 10-, 11-, or 12-membered heterocyclyl is optionally substitutedwith one, two, or three substituents, each independently selected fromthe group consisting of halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy, and hydroxy;

or, when p is 2,

R³ and R⁴ taken together with the nitrogen atom to which each isattached can form a:

i. 6-membered monocyclic heterocyclyl containing one heteroatom,optionally with one or two substituents, each independently selectedfrom the group consisting of halogen, hydroxy-(C₁-C₆ alkyl), hydroxy,oxo, and C₁-C₃ alkoxy; or

ii. 4- or 7-membered monocyclic heterocyclyl containing one or twoheteroatoms, or 7-, 8-, 9, 10-, or 11-membered bicyclic bridged, fused,or spiro heterocyclyl containing one, two, or three heteroatoms,optionally substituted with one or two substituents, each independentlyselected from the group consisting of halogen, oxo, cyano, C₁-C₃ alkyl,hydroxy, NR^(G)R^(H), and —(CH₂)_(s)C(═O)NR^(k)R^(l);

-   -   provided that when the structure of Formula (I) is

* is

and ** is

; or * is

and ** is

;

or a pharmaceutically acceptable salt thereof; and

-   -   wherein the compound of Formula (I) is not:

-   N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine;

-   4-(piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

-   4-(azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

-   1-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one;    or

-   2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane;    or

a salt thereof.

Useful compounds of Formula I′ or I include those where p is 1.

Useful compounds of Formula I′ or I include those where Z is N.

The integer n will decrease by one each time a compound of Formula I′ orI contains a variable C—R⁶, N—R⁶, or S—R⁶, and the total number of n(the total number of C—R⁶, N—R⁶, or S—R⁶ cannot exceed 3).

Useful compounds of Formula I′ or I include those where Y¹, Y², Y³, andY⁴ are each CH or C—R⁶. In certain embodiments, useful compounds ofFormula I′ or I include those where Y¹ is CH Y² is C—R₆, and Y³, and Y⁴are each CH. Useful compounds of Formula I′ or I include those where Y³is N and Y¹, Y², and Y⁴ are each CH or C—R⁶. Useful compounds of FormulaI′ or I include those where Y² is N and Y¹, Y³, Y⁴ are each CH or C—R⁶.Useful compounds of Formula I′ or I include those where Y¹ is N and Y²,Y³, and Y⁴ are each CH or C—R⁶. Useful compounds of Formula I′ or Iinclude those where Y¹ is CH, Y² is C—R⁶, Y³ is CH, and Y⁴ is CH.

Useful compounds of Formula I′ or I include those where R⁶, in eachinstance, is selected from the group consisting of halogen, hydroxy,C₁-C₃ alkoxy, C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃ alkyl, hydroxy-C₁-C₆alkoxy, hydroxy-C₁-C₃-alkyl, —O—(CH₂)_(u)—R^(bb), halo-C₁-C₃ alkoxy,—O—R^(cc)—O—R^(dd), halo- C₁—C₃ alkyl, hydroxy-C₁-C₁₀-alkyl, —O—(C₁-C₆alkyl)-R^(bb), —O—R^(bb), —S—C₁-C₃ alkyl, —S—C₁-C₃ alkyl-NR^(G1)R^(H1)and —NR^(G)R^(H); wherein, the alkyl moiety in hydroxy-C₁-C₁₀ alkoxy or—O—(C₁-C₆ alkyl)-R^(bb) is optionally substituted with cyano, hydroxy,hydroxy-C₁-C₃-alkyl, halogen, or C₁-C₃ alkoxy; R^(bb) is —NR^(G)R^(H); uis an integer from 1 to 3; R^(G) and R^(H) are each independentlyhydrogen or C₁-C₃ alkyl; and R^(cc) and R^(dd) are each independentlyC₁-C₃ alkyl. Useful compounds of Formula I′ or I include those where R⁶,in each instance, is selected from the group consisting of methoxy,ethoxy, methyl, fluoro, chloro, ethyl, —N(CH₃)₂, hydroxy, —OCH₂CH₂OH,—CH₂OH, —CH₂OCH₃, —OCH₂CH₂NH₂, —OCH₂CH₂N(CH₃)₂, —OCH₂C(CH₃)₂O H,—OCH₂CF₃, —OCHF₂, —OCF₃, —OCH₂CH₂OCH₃, —OCH₂CH₂F, —OC(CH₃)₂CH₂OH,—OCH₂CH(CH₃)O H, —OCH₂CH₂NHC(O)CH₃, —OC(CH₃)₂CH₂N(CH₃)₂, —OCH(CH₃)CH₂OH,—OCH₂CH(CH(CH₃)₂)OH, —OCH₂CH(CH₂CH₃)OH, —OCH₂C(CH₂CH₃)₂OH,—OCH₂CH₂N(CH₂CH₃)₂, —OCH(CH₃)CH₂N(CH₃)₂, —OCH₂C(O)N(CH₃)₂,—OCH₂C(CH₃)₂N(CH₃)₂, —OCH₂CH(CH₂OH)OH, —OCH₂CH₂NH(CH₃), —OCH₂CH(CF₃)OH,—OCH₂C(CH₃)(CH₂CH₃)OH, —OCH₂CH(CH₂OCH₃)OH, —OCH₂CH(CH₂F)OH,—(CH₂)₃N(CH₃)₂, —(CH₂)₃N(CH₃)H, —O(CH₂)₂S(O)₂CH₃, —O(CH₂)₂SCH₃,—(CH₂)₂C(CH₃)₂OH, and —CH₂CH₂OH. Further, useful compounds of Formula I′or I include those where R⁶, in each instance, is methoxy,—OCH₂CH₂N(CH₃)₂, —OCH₂CH₂OH, or —OCH₂C(CH₃)₂OH. Useful compounds ofFormula I′ or I include those where R⁶, in each instance, is selectedfrom the group consisting of —O—(CH₂)_(u)—R^(bb), and C₃-C₆ cycloalkyl;wherein, u is an integer from 0 to 3; R^(bb) is 4- to 7-memberedmonocyclic heterocyclyl or C₃-C₇ cycloalkyl; and wherein said cycloalkylor heterocyclyl is optionally substituted with one or two substituents,each independently selected from the group consisting of hydroxy, C₁-C₃alkoxy, and C₁-C₃ alkyl. Useful compounds of Formula I′ or I includethose where R⁶, in each instance, is selected from the group consistingof cyclopropyl and —O—(CH₂)_(u)—R^(bb); wherein, u is 0, 1, or 2; andR^(bb) is selected from the group consisting of cyclopropyl, cyclobutyl,tetrahydrofuranyl, oxetanyl, and pyrrolidinyl, each optionallysubstituted with hydroxy or methyl. Useful compounds of Formula I′ or Iinclude those where R⁶, in each instance, is selected from the groupconsisting of

where

indicates the point of attachment to Ring B. Useful compounds of FormulaI′ or I include those where R⁶ is

Useful compounds of Formula I′ or I include those where two R⁶ groups,taken together with the atom to which each is attached, form a 5- or6-membered monocyclic heterocyclyl fused with Ring B, a C₄-C₇ cycloalkylfused with Ring B, a phenyl fused with Ring B, or a 5- or 6-memberedmonocyclic heteroaryl fused with Ring B, each optionally substitutedwith one or two substituents, each independently selected from the groupconsisting of C₁-C₃ alkoxy, hydroxy, hydroxy-C₁-C₃-alkyl, C₁-C₃ alkyl,C₃-C₇ cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl. Usefulcompounds of Formula I′ or I include those where two R⁶ groups, takentogether with the atom to which each is attached, form a pyrazolyl,dioxanyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, dioxolanyl, orphenyl ring fused with Ring B, wherein said ring is optionallysubstituted with one substituent selected from the group consisting ofhydroxy, methoxy, tetrahydropyranyl, —CH₂OH, and methyl. Usefulcompounds of Formula I′ or I include those where two vicinal R⁶ groups,taken together with the atom to which each is attached, form a ringselected from the group consisting of

fused with ring B, wherein the pair of

represent the attachment of the ring with Ring B. Useful compounds ofFormula I′ or I include those where two vicinal R⁶ groups, takentogether with the atom to which each is attached, form a form a ringselected from the group consisting of

fused with Ring B. Useful compounds of Formula I′ or Formula I includethose where two vicinal R⁶ groups taken together with the atom to whicheach is attached form a ring fused with Ring B, where the bicyclic ringformed by Ring B and the two vicinal R⁶ groups is selected from thegroup consisting of

Useful compounds of Formula I′ or Formula I include those where f is 1.Useful compounds of Formula I′ or Formula I include those where f is 0,and Ring B is

Useful compounds of Formula I′ or Formula I include those where Ring Bis

wherein, n is 0 or 1; and Y² and Y³ are each independently selected fromthe group consisting of CH, N, NH, NR⁶, S, O, and CR⁶, provided thatonly one of Y^(z) and Y³ can be N, NH, NR⁶, S, or O. Useful compounds ofFormula I′ or Formula I include those where Ring B is selected from thegroup consisting of

Useful compounds of Formula I′ or Formula I include those where R⁶, ineach instance, is selected from the group consisting of C₁-C₃ alkyl andhydroxy-C₁-C₃ alkyl. Useful compounds of Formula I′ or Formula I includethose where R⁶, in each instance, is selected from the group consistingof methyl, ethyl, n-propyl, —CH₂CH₂OH, and —CH₂CH₂CH₂OH.

Useful compounds of Formula I′ or Formula I include those where n is 1.Useful compounds of Formula I′ or Formula I include those where n is 0.Useful compounds of Formula I′ or Formula I include those where n is 2,wherein one R⁶ is selected from the group consisting of methyl andmethoxy and the other R⁶ is selected from the group consisting ofmethyl, methoxy, halogen, and —OCH₂CH₂OH.

Useful compounds of Formula I′ or Formula I include those where R³ isselected from the group consisting of hydrogen, methyl, ethyl, phenyl,and —CH₂CH₂OH. Useful compounds of Formula I′ or Formula I include thosewhere R³ is selected from the group consisting of hydrogen, methyl,—CD₃, ethyl, phenyl, —CH₂CF₃, and —CH₂CH₂OH. Useful compounds of FormulaI′ or Formula I include those where R³ is methyl.

Useful compounds of Formula I′ or Formula I include those where R⁴ is a(5- to 10-membered monocyclic or fused bicyclic heteroaryl)-methyl,wherein said heteroaryl is optionally substituted with one or twosubstituents, each independently selected from the group consisting ofphenyl, C₃-C₇ cycloalkyl, and 5- to 7-membered monocyclic heterocyclyl,and wherein said phenyl, cycloalkyl, or heterocyclyl is optionallysubstituted with one or two substituents, each individually selectedfrom the group consisting of C₁-C₃ alkyl, halogen, and hydroxy. Usefulcompounds of Formula I′ or Formula I include those where R⁴ is a(6-membered heteroaryl)-methyl, wherein at least one of the ring atomsortho to the attachment point in said 6-membered heteroaryl is anitrogen. Useful compounds of Formula I′ or Formula I include thosewhere R⁴ is selected from the group consisting of pyridinyl-methyl,pyrimidinyl-methyl, benzoxazole-methyl, oxazolyl-methyl, andtriazolyl-methyl, each optionally substituted with phenyl or benzyl, andwherein said phenyl is optionally substituted with one substituentselected from the group consisting of fluoro, methyl, and chloro. Usefulcompounds of Formula I′ or Formula I include those where R⁴ is selectedfrom the group consisting of

Useful compounds of Formula I′ or Formula I include those where R⁴ is

Useful compounds of Formula I′ or Formula I include those where R⁴⁰ isselected from the group consisting of hydrogen, methyl, isopropyl,—CH₂OH, —CH₂OC(CH₃)₃, and —CH₂CH₂SCH₃; and R^(4d) is selected from thegroup consisting of hydrogen and methyl; or, R^(4c) and R^(4d) takentogether with the atom to which each is attached form a cyclopropylring. Useful compounds of Formula I′ or Formula I include those whereR^(4c) and R^(4d) are each hydrogen. Useful compounds of Formula I′ orFormula I include those where R^(4b) is hydrogen. Useful compounds ofFormula I′ or Formula I include those where R^(4a) is C₁-C₆ alkyl.Useful compounds of Formula I′ or Formula I include those where R^(4a)tert-butyl or isopropyl. Useful compounds of Formula I′ or Formula Iinclude those where R^(4a) is phenyl, optionally substituted with one ortwo substituents, each independently selected from the group consistingof halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl, hydroxy, C₁-C₃ alkoxy, C₃-C₇cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclicheterocyclyl. Useful compounds of Formula I′ or Formula I include thosewhere R^(4a) is phenyl optionally substituted with one substituentselected from the group consisting of fluoro, chloro, methyl, andmethoxy. Useful compounds of Formula I′ or Formula I include those whereR^(4a) is selected from the group consisting of

Useful compounds of Formula I′ or Formula I include those where R^(4a)is 5- to 10-membered monocyclic or fused bicyclic heteroaryl optionallysubstituted with one or two substituents, each independently selectedfrom the group consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl,hydroxy, C₁-C₃ alkoxy, C₃-C₇ cycloalkyl, and 5- to 10-memberedmonocyclic, fused bicyclic, or spiro heterocyclyl. Useful compounds ofFormula I′ or Formula I include those where R^(4a) is pyridinyl,pyrimidinyl, pyrazolyl, isothiazolyl, pyridizinyl, or quinolinyl,optionally substituted with one substituent selected from the groupconsisting of fluoro, chloro, methoxy, azepanyl, cyclopropyl, —CF₃,—OCF₃, or methyl. Useful compounds of Formula I′ or Formula I includethose where R^(a) is selected from the group consisting of

Useful compounds of Formula I′ or Formula I include those where R^(4a)is C₃-C₇ cycloalkyl, optionally substituted with one or twosubstituents, each independently selected from the group consisting ofhalogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl, hydroxy, C₁-C₃ alkoxy, C₃-C₇cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclicheterocyclyl. Useful compounds of Formula I′ or Formula I include thosewhere R^(4a) is selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentan-1-yl,optionally substituted with one or two substituents, each independentlyselected from the group consisting of methyl, —CF₃, fluoro, or hydroxy.Useful compounds of Formula I′ or Formula I include those where R^(4a)is selected from the group consisting of

Useful compounds of Formula I′ or Formula I include those where R^(4a)is a 4- to 10-membered monocyclic or fused bicyclic heterocyclyl,optionally substituted with one or two substituents, each independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃alkyl, hydroxy, C₁-C₃ alkoxy, oxo, C₃-C₇ cycloalkyl, and 5- to10-membered monocyclic or fused bicyclic heterocyclyl. Useful compoundsof Formula I′ or Formula I include those where R^(4a) is selected fromthe group consisting of tetrahydrofuranyl, pyrrolidinyl,benzo[d][1,3]dioxolyl, oxetanyl, and tetrahydropyranyl, optionallysubstituted with one or two substituents, each independently selectedfrom the group consisting of methyl, methoxy, and oxo. Useful compoundsof Formula I′ or Formula I include those where R^(4a) is selected fromthe group consisting of

Useful compounds of Formula I′ or Formula I include those where R^(4a)is (C₆-C₁₀ monocyclic or fused bicyclic aryl)-C₁-C₃ alkyl or (5- to10-membered monocyclic or fused bicyclic heteroaryl)-C₁-C₃ alkyl,optionally substituted with one or two substituents, each independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃alkyl, hydroxy, C₁-C₃ alkoxy, C₃-C₇ cycloalkyl, and 5- to 10-memberedmonocyclic, fused bicyclic heterocyclyl. Useful compounds of Formula I′or Formula I include those where R^(4a) is selected from the groupconsisting of benzyl, 2-(1-cyclobutyl-5-methyl-1H-imidazol-2-yl)ethyl,and pyridinyl-methyl. Useful compounds of Formula I′ or Formula Iinclude those where R^(4a) is selected from the group consisting of

Useful compounds of Formula I′ or Formula I include those where R^(4a)is selected from the group consisting of —C(CH₃)₂CH₂OH, —CH₂CH₂OH, and—C(CH₃)₂CH₂OCH₃. Useful compounds of Formula I′ or Formula I includethose where R^(4a) and R^(4b) taken together with the atom to which eachis attached form a 5- to 10-membered monocyclic, fused bicyclic, orbridged bicyclic heterocyclyl, optionally substituted with one or twosubstituents, each independently selected from the group consisting ofhalogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl, hydroxy, and C₁-C₃ alkoxy.Useful compounds of Formula I′ or Formula I include those where R^(4a)and R^(4b) taken together with the atom to which each is attached form apiperidinyl, morpholinyl, pyrrolidinyl, azepanyl, indolinyl,azabicyclo[3.1.1]heptanyl, or piperazinyl, optionally substituted withone or two substituents, each independently selected from the groupconsisting of methyl, fluoro, hydroxy, and methoxy. Useful compounds ofFormula I′ or Formula I include those where R^(4a) and R^(4b) takentogether with the atom to which each is attached form a

Useful compounds of Formula I′ or Formula I include those where R^(4b)and R^(4c) taken together with the atom to which each is attached form a5- to 7-membered monocyclic heterocyclyl, optionally substituted withone or two substituents, each independently selected from C₁-C₃ alkyl.Useful compounds of Formula I′ or Formula I include those where R^(4b)and R^(4c) taken together with the atom to which each is attached form apiperidin-2-one or a pyrrolidine-2-one, optionally substituted one ortwo times with methyl.

Useful compounds of Formula I′ or Formula I include those where R⁴ is

wherein R^(4g) is selected from the group consisting of C₆-C₁₀monocyclic or fused bicyclic aryl and C₁-C₃ alkyl. Useful compounds ofFormula I′ or Formula I include those where R^(4g) is selected from thegroup consisting of phenyl and methyl.

Useful compounds of Formula I′ or Formula I include those where R³ andR⁴ taken together with the nitrogen atom to which each is attached forma 7-membered monocyclic or bridged bicyclic heterocyclyl containing oneor two heteroatoms; wherein when said 7-membered heterocyclyl containsone heteroatom, said heterocyclyl is optionally substituted with one,two, or three substituents, each independently selected from the groupconsisting of oxo, halogen, hydroxy, C₁-C₃ alkoxy, cyano, and C₁-C₃alkyl; and when said 7-membered heterocyclyl contains two heteroatoms,said heteroatoms are each independently N or O, and said heterocyclyl isoptionally substituted with one, two, or three substituents, eachindependently selected from the group consisting of C₁-C₃ alkyl, cyano,oxo, halogen, halo-C₁-C₃ alkyl, and C₆-C₁₀ monocyclic or fused bicyclicaryl; and wherein said aryl is optionally substituted with one or twosubstituents, each individually selected from the group consisting ofC₁-C₃ alkoxy, hydroxy, halogen, and C₁-C₃ alkyl. Useful compounds ofFormula I′ or Formula I include those where R³ and R⁴ taken togetherwith the nitrogen atom to which each is attached form a 7-memberedheterocyclyl containing one heteroatom, wherein said heterocyclyl isoptionally substituted once with methyl or oxo; or, a 7-memberedmonocyclic or bridged bicyclic heterocyclyl containing two heteroatoms,wherein said heteroatoms are N or O, and said heterocyclyl is optionallysubstituted with one or two substituents, each independently selectedfrom the group consisting of phenyl, methyl, and oxo, and wherein saidphenyl is optionally substituted with methoxy. Useful compounds ofFormula I′ or Formula I include those where R³ and R⁴ taken togetherwith the nitrogen atom to which each is attached form a

Useful compounds of Formula I′ or Formula I include those where R³ andR⁴ taken together with the nitrogen atom to which each is attached forma 10- or 11-membered fused bicyclic heterocyclyl containing oneheteroatom, or a 12-membered bicyclic fused and bridged heterocyclyl,each optionally substituted with one, two, or three substituents, eachindependently selected from the group consisting of C₁-C₃ alkyl, C₁-C₃alkoxy, hydroxy, and halogen. Useful compounds of Formula I′ or FormulaI include those where R³ and R⁴ taken together with the nitrogen atom towhich each is attached form a

Useful compounds of Formula I′ or Formula I include those where R³ andR⁴ taken together with the nitrogen atom to which each is attached forma 4- or 6-membered monocyclic heterocyclyl containing one heteroatom;wherein, said 4-membered monocyclic heterocyclyl is optionallysubstituted with —(CH₂)_(s)C(═O)NR^(k)R^(l); wherein, s is 0, 1, or 2;R^(k) is hydrogen or C₁-C₃ alkyl; and R^(l) is selected from the groupconsisting of hydrogen, methyl, phenyl, cyclopentyl, and cyclohexyl;and, said 6-membered monocyclic heterocyclyl is optionally substitutedwith one or two substituents, each independently selected from the groupconsisting of C₁-C₃ alkoxy, oxo, halogen, cyano, and —NR^(q)R^(w);wherein, R^(q) is hydrogen or C₁-C₃ alkyl; R^(w) is C₆-C₁₀ monocyclic orfused bicyclic aryl or C₃-C₇ cycloalkyl, wherein said aryl or cycloalkylis optionally substituted with one or two substituents, eachindependently selected from the group consisting of halogen, C₁-C₃alkyl, hydroxy, and C₁-C₃ alkoxy. Useful compounds of Formula I′ orFormula I include those where R³ and R⁴ taken together with the nitrogenatom to which each is attached form a

Useful compounds of Formula I′ or Formula I include those where R^(x),in each instance, is methyl. Useful compounds of Formula or Formula Iinclude those where m is 0. Useful compounds of Formula I′ or Formula Iinclude those where m is 2.

The subject matter described herein includes the following compounds inTable 1, or pharmaceutically acceptable salts thereof:

TABLE 1 Where the mass for a compound is not provided in Table 1, themass can be found for the compound in the synthetic examples. MassCompound Found No. Structure IUPAC Name (M + 1) 1

10-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]-10-azatricyclo[6.3.1.0{circumflex over ( )}{2,7}]dodeca- 2,4,6-triene 355 2

7-methoxy-3-[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-3- benzazepine 373.1 3

6-methoxy-3-[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-3- benzazepine 373 4

1-(3-methoxyphenyl)-4-[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4- diazepane 402.1 5

N-(pyridin-2-yl)-2-{[2-(pyridin-2- yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 347.1 6

N-(2-fluroophenyl)-2-{[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 364.1 7

2-{[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-N-(quinolin-7- yl)acetamide 397.1 8

N-tert-butyl-2-{[2-(pyrimidin-4- yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide 327.2 9

N-tert-butyl-2-{[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino}acetamide 325.1 10

N-tert-butyl-2-{[2-(pyridin-2-yl)- 5,6,7,8-tetrahydroquinazolin-4-yl]amino}acetamide 340.1 11

N-(4-methoxyphenyl)-1-[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]piperidin-3-amine 402.4 12

N-tert-butyl-2-{[2-(5- methoxypyrazin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 371.2 13

2-[4-(azepan-1-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-2-yl]-N,N-dimethylpyridin-4-amine 338.1 14

1-[2-(4-methylpyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]azepane 309.2 15

N-(2-methoxyphenyl)-2- {methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 390.3 16

N-tert-butyl-2-{methyl[2-(pyridin- 2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4- yl]amino}acetamide 339.2 17

N-cyclohexyl-1-{methyl[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}cyclopropane-1- carboxamide 392.2 18

2-{4-[(5aS,8aS)-octahydro-2H- cyclopenta[b][1,4]oxazepin-5-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-2- yl}pyridine 19

N-tert-butyl-2-methyl-2- {methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}propanamide 368.1 20

N-tert-butyl-2-{phenyl[2-(pyridin- 2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}propanamide 415.8 21

2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-N-(quinolin-7- yl)acetamide 411.2 22

N-(2-fluorophenyl)-2-{methyl[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 378.2 23

N-tert-butyl-2-{methyl[2-(pyridin- 2-yl)-5,6,7,8-tetrahydroquinazolin-4- yl]amino}acetamide 354.2 24

N-tert-butyl-2-{methyl[2-(4- methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 354.2 25

2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-N-(1- methylcyclohexyl)acetamide 380.3 26

2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-N-(oxan-3- yl)acetamide 368.2 27

N-benzyl-2-{methyl[2-(pyridin-2- yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide 374.2 28

N-tert-butyl-2-{[2-(5- hydroxypyrazin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 357.2 29

N-cyclohexyl-1-[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]azetidine-3-carboxamide 378.3 30

N-cyclohexyl-1-[2-(4- methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]azetidine-3-carboxamide 392.4 31

N-(1-methyl-2-oxopyrrolidin-3- yl)-2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 381.3 32

N-(2,2-difluoro-2H-1,3- benzodioxol-5-yl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}acetamide440.3 33

N-tert-butyl-2-{[2-(pyrimidin-2- yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide 327.2 34

N-tert-butyl-2-{[2-(4- methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 370.2 35

N-tert-butyl-2-({2-[4- (methoxymethyl)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 384.2 36

N-tert-butyl-2-{ethyl[2-(pyridin-2- yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 354.2 37

N-tert-butyl-2-[(2- hydroxyethyl)[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino]acetamide 370.2 38

2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-N-[(pyridin-2- yl)methyl]acetamide 375.2 39

N-tert-butyl-2-({2-[6-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 400.2 40

N-tert-butyl-2-({2-[5-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 400.3 41

N-tert-butyl-2-({2-[4- (hydroxymethyl)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 370.2 42

N-tert-butyl-2-{methyl[2-(4- methylpyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4- yl]amino}acetamide 368.2 43

N-tert-butyl-2-({2-[5-(2- hydroxyethyl)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 384.2 44

N-tert-butyl-2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 400.2 45

2-{4-[(5aS,8aS)-octahydro-2H- cyclopenta[b][1,4]oxazepin-5-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-2-yl}-4- methylpyridine 46

1-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]azepan-2-one47

4-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]-1,4-diazepan-2-one 310 48

2-{4-[(5aS,8aR)-octahydro-2H- cyclopenta[b][1,4]oxazepin-5-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-2- yl}pyridine 49

2-{4-[(5aS,8aR)-octahydro-2H- cyclopenta[b][1,4]oxazepin-5-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-2-yl}-4- methylpyridine 50

1-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]-1,4-diazepan-5-one 309.9 51

(2R)-N-tert-butyl-2-{methyl[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}propanamide 354.4 52

(2S)-N-tert-butyl-2-{methyl[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}propanamide 354.4 53

1-[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]azepane 325.1 54

2-{4-[(5aS,8aR)-octahydro-2H- cyclopenta[b][1,4]oxazepin-5-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-2-yl}-4- methoxypyridine 55

(3R)-6,6-dimethyl-3-{[2-(pyridin- 2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}piperidin-2-one 338.2 56

(3S)-6,6-dimethyl-3-{[2-(pyridin- 2-yl)-5H,6H,7H-cyclopenta[d]pyrimdiin-4- yl]amino}piperidin-2-one 338.2 57

N-tert-butyl-2-{[2-(4- cyclopropylpyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 380.2 58

N-tert-butyl-2-{[2-(4- fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 358.1 59

N-tert-butyl-2-{methyl[2-(6- methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 354.3 60

N-tert-butyl-2-{[2-(4,5- dimethylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 368.2 61

N-(1-hydroxy-2-methylpropan-2- yl)-2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 356.2 62

N-(1-hydroxy-2-methylpropan-2- yl)-2-{methyl[2-(4-methylpyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}acetamide 370.1 63

N-(4-hydroxy-2-methylbutan-2- yl)-2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 370.3 64

N-cyclopentyl-2-{methyl[2-(4- methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 366.2 65

2-{methyl[2-(4-methylpyridin-2- yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-N-(3-methyloxolan-3- yl)acetamide 382.3 66

N-(3-fluorophenyl)-2-{methyl[2- (4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 392.1 67

N-tert-butyl-2-{methyl[2- (pyrimidin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4- yl]amino}acetamide 340.1 68

N-tert-butyl-2-{methyl[2-(4- methylpyridin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4- yl]amino}acetamide 353.2 69

N-[2-(1-cyclobutyl-5-methyl-1H- imidazol-2-yl)ethyl]-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}acetamide446.2 70

N-[5-(azepan-1-yl)-1,3,4- thiadiazol-2-yl]-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}acetamide465.3 71

1-[2-(3-fluoropyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]azepane 312.4 72

5-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]-2-oxa-5-azabicyclo[2.2.1]heptane 295 73

N-methyl-2-(pyridin-2-yl)-N- [(pyridin-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine 317.9 74

N-(3-fluorophenyl)-2-{methyl[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 379 75

N-(4-methoxyphenyl)-2- {methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 390.1 76

1-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]-1,2,3,4-tetrahydroquinoline 329.1 77

2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-N-phenylacetamide 360 78

N-cyclohexyl-2-{methyl[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 366 79

2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-N-(oxan-4- yl)acetamide 368.1 80

N-ethyl-2-(pyridin-2-yl)-N- [(pyrimidin-2-yl)methyl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4-amine 333 81

N-methyl-2-(pyridin-2-yl)-N- [(pyrimidin-2-yl)methyl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4-amine 319.1 82

N-[(1,3-benzoxazol-2-yl)methyl]- N-methyl-2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4-amine 358 83

3-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-3- benzazepine 343 84

N-(2-methoxyethyl)-N-methyl-2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine 285 85

1-methyl-4-[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4- diazepane 310.1 86

2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-1-(morpholin-4- yl)ethan-1-one 354 87

N-methyl-N-(2-phenoxyethyl)-2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine 347 88

2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-1-(piperidin-1-yl)ethan- 1-one 352.1 89

N-tert-butyl-2-{methyl[2-(pyridin- 2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 340 90

N-tert-butyl-2-{methyl[2-(pyridin- 2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}propanamide 354.4 91

N-cyclohexyl-2-{methyl[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}propanamide 380 92

1-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]azepane 295.293

4-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]-1,4-oxazepane 297.2 94

1-[2-(1,3-thiazol-4-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]azepane301.2 95

3-{methyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-1-phenylpyrrolidin-2- one 386.3 96

1-[2-(4-chloropyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]azepane 329.3 97

1-[2-(1-methyl-1H-imidazol-4-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]azepane 298.2 98

2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-N-[1- (trifluoromethyl)cyclopropyl]aceta- mide 392 99

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-[1- (trifluoromethyl)cyclopropyl]aceta- mide 421.7100

N-tert-butyl-2-{[2-(4-ethylpyridin- 2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 368.2 101

(2R)-N-tert-butyl-2-{[2-(4- methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}propanamide 384.4 102

N-tert-butyl-2-({2-[4- (dimethylamino)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 383.2 103

N-tert-butyl-2-{methyl[2-(3- methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 354.2 104

N-tert-butyl-2-{methyl[2-(5- methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 354.1 105

2-{methyl[2-(4-methylpyridin-2- yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-N-(1- methylcyclopentyl)acetamide 380.2 106

N-tert-butyl-2-{methyl[2- (pyrimidin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 341.2 107

N-tert-butyl-2-({2-[5-(2- hydroxyethyl)-1,3-thiazol-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 390.2 108

(2R)-N-cyclohexyl-2-{ethyl[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}propanamide 380.4 109

(2R)-N-(3,3-difluorocyclobutyl)- 2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}propanamide 388.3 110

N-tert-butyl-2-[methyl(2-{1H- pyrazolo[3,4-c]pyridin-5-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]acetamide 380.2 111

2-{methyl[2-(1-methyl-1H- imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}-N-[1-(trifluoromethyl)cyclopropyl]aceta- mide 395.2 112

(2R)-N-tert-butyl-2-{methyl[2-(1- methyl-1H-imidazol-4-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}propanamide 357.4 113

N-tert-butyl-2-({2-[4-(2- hydroxyethyl)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 384.2 114

(2R)-N-tert-butyl-3-methyl-2- {methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}butanamide 382 115

(2S)-N-tert-butyl-3-methyl-2- {methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}butanamide 382 116

(2R)-N-tert-butyl-2-{methyl[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}-4- (methylsulfanyl)butanamide 414117

(2S)-N-tert-butyl-2-{methyl[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}-4- (methylsulfanyl)butanamide 414.1118

(2R)-N-cyclohexyl-2-{methyl[2- (1-methyl-1H-imidazol-4-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}propanamide 383.2 119

(2R)-N-cyclohexyl-2-{[2-(4- methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}propanamide 410.1 120

(2S)-3-(tert-butoxy)-N-tert-butyl- 2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}propanamide 426.1 121

(2R)-3-(tert-btuoxy)-N-tert-butyl- 2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}propanamide 426.1 122

N-tert-butyl-2-[(2-{2H,3H- [1,4]dioxino[2,3-c]pyridin-7-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 398.2 123

(2S)-N-tert-butyl-3-hydroxy-2- {methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}propanamide 369.9 124

(2R)-N-tert-butyl-3-hydroxy-2- {methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}propanamide 370 125

N-tert-butyl-2-{methyl[2-(1- methyl-1H-imidazol-4-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 343.2 126

N-tert-butyl-2-{ethyl[2-(4- methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 384.1 127

N-(6-fluoropyridin-3-yl)-2- {methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 379.1 128

N-(6-fluoropyridin-3-yl)-2-{[2-(4- methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 409.2 129

N-(6-fluoropyridin-3-yl)-2- {methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}acetamide382.2 130

(3R)-3-{methyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-1-phenylpyrrolidin-2- one 386 131

(3S)-3-{methyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-1-phenylpyrrolidin-2- one 386 132

(3R)-3-{[2-(4-methoxypyridin-2- yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-1- phenylpyrrolidin-2-one 415.9 133

N-(2-hydroxyethyl)-2-{[2-(4- methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 358.2 134

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(oxan-4- yl)acetamide 398.2 135

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(oxolan-3- yl)acetamide 384.1 136

N-(1-hydroxy-2-methylpropan-2- yl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 386.2137

N-cyclohexyl-2-{[2-(4- methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 396.2 138

N-(3-fluorophenyl)-2-{[2-(4- methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 408.2 139

N-(1-methoxy-2-methylpropan-2- yl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 400.2140

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(oxan-4- yl)acetamide428.2 141

N-[(1R,2R)-2- hydroxycyclohexyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 412.3 142

N-cyclohexyl-2-{methyl[2-(1- methyl-1H-imidazol-4-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 369.2 143

N-(1-hydroxy-2-methylpropan-2- yl)-2-{ethyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}acetamide359.2 144

N-cyclohexyl-2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 426.2 145

N-tert-butyl-2-{[2-(4,5- dimethoxypyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 400.2 146

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(3- methyloxolan-3-yl)acetamide 398 147

2-{methyl[2-(1-methyl-1H- imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}-N-(3-methyloxolan-3- yl)acetamide371 148

N-(1-hydroxy-2-methylpropan-2- yl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide 416.2 149

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(oxolan-3- yl)acetamide414.2 150

N-cyclopentyl-2-{methyl[2-(1- methyl-1H-imidazol-4-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 355.2 151

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6- methoxypyridin-3-yl)acetamide 421.2 152

N-(5-methoxypyridin-2-yl)-2-{[2- (4-methoxypyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 421.2 153

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(2- methoxypyrimidin-5-yl)acetamide 422.2 154

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(1-methyl- 1H-pyrazol-4-yl)acetamide 394.2 155

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimdiin-4-yl](methyl)amino}-N-(1- methylcyclopentyl)acetamide 396.2 156

N-tert-butyl-2-{[2-(4- methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}-N- methylacetamide 384.2 157

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N,N- dimethylacetamide 342.2 158

N-tert-butyl-2-{[2-(4- cyanopyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 365.2 159

N-tert-butyl-2-({2-[4- (cyclopropylmethoxy)pyridin-2- yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 410.2 160

N-tert-butyl-2-{methyl[2-(1- methyl-1H-pyrazlo-3-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 343.2 161

2-{methyl[2-(1-methyl-1H- imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}-N-(1- methylcyclopentyl)acetamide369.2 162

N-tert-butyl-2-{methyl[2-(1- methyl-1H-imidazol-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 343.2 163

N-tert-butyl-2-{methyl[2-(1,3- oxazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 330.2 164

N-tert-butyl-2-{methyl[2-(1,3- oxazol-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 330.2 165

N-tert-butyl-2-{[2-(isoquinolin-3- yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 390.2 166

N-tert-butyl-2-[(2-{imidazo[1,2- a]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 379.2 167

N-(3-fluorophenyl)-2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 438.2 168

N-[(1R,2S)-2- hydroxycyclohexyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 412.2 169

N-[(1S,2R)-2- hydroxycyclohexyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 412.2 170

N-[(1R,2S)-2- hydroxycyclopentyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 398.2 171

N-[(1S,2R)-2- hydroxycyclopentyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 398.2 172

N-[(1R,2R)-2- hydroxycyclopentyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 398.2 173

N-[(1S,2S)-2- hydroxycyclopentyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 398.2 174

N-tert-butyl-2-({2-[4-(2-hydroxy- 2-methylpropoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 428.2 175

N-tert-butyl-2-{methyl[2- (pyridazin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 341.2 176

N-tert-butyl-2-[methyl(2-{1H- pyrazolo[4,3-c]pyridin-6-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]acetamide 380.2 177

2-[methyl({2-[4-(2,2,2- trifluoroethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl})amino]-N-(1-methyl-1H-pyrazol-4-yl)acetamide 462.1 178

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(pyrimidin- 5-yl)acetamide 392.1 179

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimdiin-4- yl}(methyl)amino)-N-(1-methylcyclopentyl)acetamide 426.3 180

N-tert-butyl-2-{[2-(4- methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 370.2 181

N-tert-butyl-2-{[2-(3- hydroxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 356.2 182

N-tert-butyl-2-{[2-(1H-imidazol- 4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 329.2 183

(2R)-N-tert-butyl-2-[methyl(2- {1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H- cyclopenta[d]pyrimidni-4- yl)amino]propanamide 394.2 184

2-[methyl(2-{1H-pyrazolo[3,4- c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]-N-(1- methylcyclopentyl)acetamide406.2 185

2-[methyl(2-{1H-pyrazolo[3,4- c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]-N-(3-methyloxolan-3- yl)acetamide408.2 186

N-(2-methoxypyrimidin-5-yl)-2- {methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}acetamide395.2 187

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide 451.2 188

1-(4-methoxyphenyl)-4-[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4- diazepan-2-one 416.1 189

N-(4-fluorophenyl)-2-{[2-(4- methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 408.1 190

N-(5-methoxypyridin-2-yl)-2- {methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}acetamide394.2 191

N-tert-butyl-2-({2-[4-(2- hydroxyethoxy)-5-methylpyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide414.2 192

N-tert-butyl-2-{[2-(4-methoxy-5- methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 384.2 193

N-tert-butyl-2-{[2-(1-ethyl-1H- imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 357.2 194

N-tert-butyl-2-{[2-(1-ethyl-1H- imidazol-5-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 357.2 195

N-tert-butyl-2-({2-[1-(2- hydroxyethyl)-1H-imidazol-4-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 373.3 196

N-tert-butyl-2-({2-[1-(2- hydroxyethyl)-1H-imidazol-5-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 373.3 197

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(2-methoxypyrimidin-5-yl)acetamide 452.2 198

N-(4-fluorophenyl)-2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 438.2 199

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methylpyridin-3-yl)acetamide 435.2 200

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6- methylpyridin-3-yl)acetamide 405.2 201

N-(6-methoxypyridin-3-yl)-2- {methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}acetamide394.2 202

N-(4-fluorophenyl)-2-{methyl[2- (1-methyl-1H-imidazol-4-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 381.2 203

4-(4-methoxyphenyl)-1-[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4- diazepan-5-one 416.1 204

(2R)-2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-N-(1- methylcyclopropyl)propanamide 352.1 205

(3S)-3-{[2-(4-methoxypyridin-2- yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-1- phenylpyrrolidin-2-one 416.3 206

(3S)-1-(4-fluorophenyl)-3- {methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}pyrrolidin-2-one 404.2 207

(3S)-3-{methyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-1-(1- methylcyclopentyl)pyrrolidin-2- one 392.2 208

(3S)-3-{methyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-1-(pyridin-4- yl)pyrrolidin-2-one 386.9 209

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(5-methoxypyridin-2-yl)acetamide 451.2 210

2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide 479.3 211

N-tert-butyl-2-[methyl(2-{4- [(oxetan-3-yl)methoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide 426.2 212

(2R)-N-tert-butyl-2-({2-[4- (difluoromethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-4-(methylsulfanyl)butanamide 480.4 213

2-({2-[4- (difluoromethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(1-methyl-1H-pyrazol-4-yl)acetamide 429.9 214

2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(5-methoxypyridin-2-yl)acetamide 479.3 215

2-({2-[4- (cyclopropylmethoxy)pyridin-2- yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(1-methyl-1H-pyrazol-4-yl)acetamide 434.1 216

2-({2-[4- (difluoromethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-fluoropyridin-3-yl)acetamide 445.1 217

2-({2-[4- (difluoromethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(5-methoxypyridin-2-yl)acetamide 456.9 218

2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(1-methyl- 1H-pyrazol-4-yl)acetamide 414.0 219

N-(6-methoxypyridin-3-yl)-2- [methyl(2-{1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide431.2 220

N-(1-methyl-1H-pyrazol-4-yl)-2- {methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}acetamide367.2 221

N-(6-fluoropyridin-3-yl)-2-{[2- (isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 429.1 222

2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6- methylpyridin-3-yl)acetamide 425.2 223

2-{[2-(4-ethoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6- methoxypyriidn-3-yl)acetamide 435.2 224

2-({2-[4- (cyclopropylmethoxy)pyridin-2- yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide 461.3 225

2-({2-[4- (difluoromethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide 457.2 226

N-tert-butyl-2-[(2-{2H- [1,3]dioxolo[4,5-c]pyridin-6-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 384.2 227

2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6- methoxypyridin-3-yl)acetamide 441.3 228

2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(pyridin-3- yl)acetamide 411.3 229

N-(6-methoxypyridin-3-yl)-2- [methyl({2-[4-(2,2,2-trifluoroethoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl})amino]acetamide 489.2 230

N-(6-methoxypyridin-3-yl)-2- [methyl({2-[4-(trifluoromethoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl})amino]acetamide 475.3 231

2-[methyl({2-[4- (trifluoromethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl})amino]-N-(1-methyl-1H-pyrazol-4-yl)acetamide 448.2 232

2-[methyl(2-{1H-pyrazolo[3,4- c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]-N-(1-methyl-1H-pyrazol-3-yl)acetamide 404.3 233

2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(5- methoxypyridin-2-yl)acetamide 441.3 234

2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-[6- (trifluoromethoxy)pyridin-3- yl]acetamide 495.2235

2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(5- methylpyridin-3-yl)acetamide 425.2 236

2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(1-methyl- 1H-imidazol-4-yl)acetamide 414.3 237

2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(1-methyl- 1H-pyrazol-3-yl)acetamide 414.3 238

2-({2-[4-(2- methoxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methoxypyiridin-3-yl)acetamide 465.3 239

N-tert-butyl-2-({2-[4-(2- methoxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 414.3 240

N-(5-fluoropyridin-3-yl)-2-{[2- (isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 429.2 241

N-tert-butyl-2-({2-[4-(2- fluoroethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 402.3 242

2-({2-[4-(2-fluoroethoxy)pyridin- 2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide 453.3 243

2-({2-[4-(2-fluoroethoxy)pyridin- 2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(1-methyl-1H-pyrazol-4-yl)acetamide 426.3 244

N-(6-methoxypyridin-3-yl)-2- {methyl[2-(1,7-naphthyridin-6-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}acetamide 442.2 245

N-tert-butyl-2-[methyl({2-[4- (oxetan-3-yloxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl})amino]acetamide 412 246

(2R)-N-(6-methoxypyridin-3-yl)- 3-methyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}butanamide 433.2 247

(2S)-N-(6-methoxypyridin-3-yl)- 3-methyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}butnamide 433.2 248

(2R)-3-methyl-N-(1-methyl-1H- pyrazol-4-yl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}butanamide406.2 249

(2S)-3-methyl-N-(1-methyl-1H- pyrazol-4-yl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}butanamide406.2 250

(2R)-2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6- methoxypyridin-3-yl)propanamide 455.2 251

(2R)-N-(3-fluorophenyl)-2-({2-[4- (2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)propanamide 452.3252

N-(3-fluorophenyl)-2-[methyl(2- {4-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)amino]acetamide 491.3 253

N-(6-methoxypyridin-3-yl)-2- [methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl})amino]acetamide 463.3 254

2-[methyl({2-[4-(oxetan-3- yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl})amino]-N-(1-methyl-1H-pyrazol-4-yl)acetamide 436.2 255

2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-1-(piperidin-1- yl)ethan-1-one 402.2 256

2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-1-(4- methylpiperazin-1-yl)ethan-1-one 417.3 257

N-(6-methoxypyridin-3-yl)-2- {methyl[2-(1,6-naphthyridin-7-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}acetamide 442.2 258

N-(6-methoxypyridin-3-yl)-2- {methyl[2-(2,6-naphthyridin-3-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}acetamide 442.2 259

2-{[2-(4-ethoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(2- methoxypyrimidin-5-yl)acetamide 436.2 260

2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(2-methoxypyrimidin-5-yl)acetamide 480.2 261

N-tert-butyl-2-{[2-(6- methoxyisoquinolin-3-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 420.2 262

N-tert-butyl-2-{[2-(7- methoxyisoquinolin-3-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 420.2 263

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-1-(piperidin-1-yl)ethan-1-one 412.3 264

N-(6-fluoropyridin-3-yl)-2- [methyl({2-[1-(oxan-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl})amino]acetamide 503.2 265

N-(5-methoxypyridin-2-yl)-2- [methyl(2-{1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide431.1 266

N-(6-fluoropyridin-3-yl)-2- [methyl(2-{1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide419.0 267

2-[methyl(2-{1H-pyrazolo[3,4- c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]-N-(6-methylpyridin-3- yl)acetamide415.1 268

N-(6-methoxypyridin-3-yl)-2- {methyl[2-(2,7-naphthyridin-3-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}acetamide 442.3 269

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(4-methoxyphenyl)acetamide 450.2 270

2-({2-[5- (hydroxymethyl)isoquinolin-3-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methylpyridin-3-yl)acetamide 455.2 271

N-(3-fluorophenyl)-2-{methyl[2- (1-methyl-1H-imidazol-4-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 381.2 272

N-(3-methoxyphenyl)-2- {methyl[2-(1-methyl-1H- imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 393.2 273

(2R)-2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(pyridazin- 4-yl)propanamide 426.7 274

(2R)-2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-[6- (trifluoromethyl)pyridin-3- yl]propanamide 493.7275

N-(1-hydroxy-2-methylpropan-2- yl)-2-({2-[1-(3-hydroxypropyl)-1H-imidazol-4-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide 403.3 276

2-[(2-{4-[(1-hydroxy-2- methylpropan-2-yl)oxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(2-methoxypyrimidin-5-yl)acetamide 480.3 277

(2R)-N-(3-fluorophenyl)-2- {methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}propanamide395.2 278

(2R)-N-(3-methoxyphenyl)-2- {methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}propanamide407.2 279

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(3-methoxyphenyl)acetamide 450.2 280

N-(3-fluorophenyl)-2-({2-[4-(2- hydroxy-2- methylpropoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 466.2 281

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(1-methyl- 6-oxo-1,6-dihydropyridin-3- yl)acetamide421.2 282

2-[(2-{2H,3H-[1,4]dioxino[2,3- c]pyridin-7-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(3- fluorophenyl)acetamide436.2 283

2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-[5- (trifluoromethoxy)pyridin-3- yl]acetamide 495.2284

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(5-methylpyrazin-2-yl)acetamide 436.2 285

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methoxypyridazin-3-yl)acetamide 452.2 286

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methylpyridazin-3-yl)acetamide 436.2 287

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(1-methyl- 2-oxo-1,2-dihydropyridin-4- yl)acetamide421.2 288

2-[methyl(2-{1H-pyrazolo[3,4- c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]-N-[6- (trifluoromethyl)pyridin-3-yl]acetamide 469.1 289

N-(4-fluorophenyl)-2-[methyl(2- {1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide 418.1 290

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(5-methoxypyrazin-2-yl)acetamide 452.3 291

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(2-methylpyrimidin-5-yl)acetamide 436.2 292

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(3- methylphenyl)acetamide434.2 293

2-({2-[4-(2-aminoethoxy)pyridin- 2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(3- fluoropehnyl)acetamide437.2 294

2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(3- fluorophenyl)acetamide465.3 295

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(5-methoxypyrimidin-2-yl)acetamide 452.3 296

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(1-methyl-1H-pyrazol-4-yl)acetamide 424.2 297

2-({2-[6- (hydroxymethyl)isoquinolin-3-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methylpyridin-3-yl)acetamide 455.2 298

2-{[2-(5-fluoropyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6- methylpyridin-3-yl)acetamide 393.1 299

N-tert-butyl-2-{[2-(5- fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 358.1 300

N-tert-butyl-2-{[2-(5- chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 374.7, 376.7 301

N-tert-butyl-2-[methyl(2- {[1,3]thiazolo[4,5-c]pyridin-6-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]acetamide 397.2 302

2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methylpyridin-3-yl)acetamide 463.3 303

N-tert-butyl-2-{[2-(5-fluoro-4- methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 372.2 304

N-(6-methoxypyridin-3-yl)-2- [methyl(2-{[1,3]thiazolo[4,5-c]pyridin-6-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide448.2 305

(2R)-N-tert-butyl-2-[methyl({2- [4-(oxetan-3-yloxy-pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl})amino]propanamide 426.3 306

2-{[2-(5-fluoro-4-methoxypyridin- 2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}-N-(6-methylpyridin-3-yl)acetamide 423.1 307

N-(3-fluorophenyl)-2-[(2-{4-[(1- hydroxycyclopropyl)methoxy]pyri-din-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide464.2 308

N-(6-cyclopropylpyridin-3-yl)-2- ({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide461.2 309

(2R)-2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)propanamide 465.3 310

(2R)-2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(1-methyl-1H-pyrazol-4-yl)propanamide 438.2 311

(2R)-N-tert-butyl-2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)propanamide 414.3 312

(2R)-N-(6-methoxypyridin-3-yl)- 2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl})amino]propanamide 477.3 313

N-(4-fluorophenyl)-2-[methyl(2- {1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide432.1 314

N-(4-fluorophenyl)-2-[methyl(2- {2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide432.1 315

2-({2-[4-({[1-(3-fluorophenyl)- 1H-1,2,4-triazol-5-yl]methyl}(methyl)amino)- 5H,6H,7H- cyclopenta[d]pyrimidin-2-yl]pyridin-4-yl}oxy)ethan-1-ol 462.2 316

(2R)-2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methylpyridin-3-yl)propanamide 449.3 317

N-tert-butyl-2-[methyl(2-{4-[(3S)- oxolan-3-yloxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide 426.2 318

N-tert-butyl-2-[methyl(2-{4- [(3R)-oxolan-3-yloxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide 426.3 319

2-({2-[4-({[4-(difluorophenyl)- 4H-1,2,4-triaozl-3-yl]methyl}(methyl)amino)- 5H,6H,7H- cyclopenta[d]pyrimidin-2-yl]pyridin-4-yl}oxy)ethan-1-ol 462.2 320

(3S)-1-(3-fluorophenyl)-3-({2-[4- (2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)piperidin-2-one478.3 321

(3R)-1-(3-fluorophenyl)-3-({2-[4- (2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)piperidin-2-one478.2 322

N-tert-butyl-N-methyl-2- [methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl})amino]acetamide 426.3 323

2-[methyl({2-[4-(oxetan-3- yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl})amino]-1-(piperidin-1- yl)ethan-1-one424.3 324

2-[methyl({2-[4-(oxetan-3- yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl})amino]-N-(6-methylpyridin-3- yl)acetamide447.2 325

N-(4-chlorophenyl)-2-[methyl({2- [4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl})amino]acetamide 466.2 326

2-[methyl({2-[4-(oxetan-3- yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl})amino]-N-(4- methylphenyl)acetamide 446.2327

N-(4-methoxyphenyl)-2- [methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl})amino]acetamide 462.2 328

N-tert-butyl-2-[methyl(2- {[1,3]thiazolo[5,4-c]pyridin-6-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]acetamide 397.2 329

N-(6-methoxypyridin-3-yl)-2- [methyl(2-{[1,3]thiazolo[5,4-c]pyridin-6-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide448.2 330

2-[(2-{4-[(1- hydroxycyclopropyl)methoxy]pyri- din-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(6-methylpyridin-3-yl)acetamide 461.2 331

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]-5,5- dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methylpyridin-3-yl)acetamide 463.3 332

N-tert-butyl-2-{methyl[2-(4- {[(2S,3S)-2-methyloxetan-3-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide 426.3 333

N-tert-butyl-2-{methyl[2-(4- {[(2R,3S)-2-methyloxetan-3-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide 426.3 334

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(4- methoxyphenyl)-N-methylacetamide 464.2 335

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-1-(5-methoxy-2,3-dihydro-1H-indol-1-yl)ethan- 1-one 476.2 336

N-tert-butyl-2-[methyl(2-{2- methyl-2H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide394.1 337

2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-[1-(trifluoromethyl)cyclopropyl]aceta- mide 480.2 338

2-[methyl({2-[4-(oxetan-3- yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl})amino]-N-[1-(trifluoromethyl)cyclopropyl]aceta- mide 464.2 339

N-(4-chloropehnyl)-2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 454.2 340

N-{bicyclo[1.1.1]pentan-1-yl}-2- [methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl})amino]acetamide 422.2 341

N-tert-butyl-2-[(2-{furo[3,2- c]pyridin-6-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 380.2 342

2-[methyl(2-{4-[(3R)-oxolan-3- yoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]-1-(piperidin-1-yl)ethan- 1-one 438.3343

2-[methyl(2-{4-[(3S)-oxolan-3- yloxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]-1-(piperidin-1-yl)ethan- 1-one 438.3344

2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(6-methoxypyridin-3-yl)acetamide 478.3 345

N-(3-fluorophenyl)-2-[methyl(2- {4-[(1s,3s)-3-hydroxycyclobutoxy]pyridin-2- yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)amino]acetamide 464.2 346

N-(6-methoxypyridin-3-yl)-2- [methyl(2-{4-[(3R)-oxolan-3-yloxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)amino]acetamide 477.2 347

N-(6-methoxypyridin-3-yl)-2- [methyl(2-{4-[(3S)-oxolan-3-yloxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4-ylamino]acetamide 477.3 348

N-tert-butyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 427.3 349

N-{bicyclo[1.1.1]pentan-1-yl}-2- ({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide410.3 350

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(3-methyl-1,2-thiaozl-5-yl)acetamide 441.2 351

2-({2-[4-({[1-(3-fluorophenyl)- 1H-1,2,4-triazol-3-yl]methyl}(methyl)amino)- 5H,6H,7H- cyclopenta[d]pyrimidin-2-yl]pyridin-4-yl}oxy)ethan-1-ol 462.3 352

N-tert-butyl-2-[methyl({2-[4-(1- methyl-1H-pyrazol-4-yl)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl})amino]acetamide 420.3 353

N-(1-cyclopropyl-1H-pyrazol-4- yl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide 450.2 354

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-1-(pyrrolidin-1-yl)ethan-1-one 398.2 355

1-(4,4-difluoropiperidin-1-yl)-2- ({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)ethan-1-one448.3 356

2-({2-[4-(2- acetamidoethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(3- fluorophenyl)acetamide479.1 357

1-(azepan-1-yl)-2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)ethan-1-one 426.3 358

1-(azepan-1-yl)-2-[methyl({2-[4- (oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl})amino]ethan-1-one 438.3 359

1-(4-fluoropiperidin-1-yl)-2-({2- [4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)ethan-1-one430.2 360

N-tert-butyl-2-[ethyl({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl})amino]acetamide 414.3 361

N-tert-butyl-2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]-5,5-dimethyl-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide428.3 362

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]-5,5- dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-1-(piperidin-1-yl)ethan-1-one 440.3 363

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]-5,5- dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide 479.3 364

1-{3-azabicyclo[3.1.1]heptan-3- yl}-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl}(methyl)amino)ethan-1-one 424.2 365

N-tert-butyl-2-[(2-{furo[2,3- c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 380.3 366

N-tert-butyl-2-[(2-{4-[(2R)-2- hydroxypropoxy]pyridin-2-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 414.3 367

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(2-methylbutan-2-yl)acetamide 414.3 368

1-(2,2-dimethylpyrrolidin1--yl)-2- ({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)ethan-1-one426.3 369

N-tert-butyl-2-({2-[4-(2- acetamidoethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 441.3 370

N-tert-butyl-2-[(2-{4-[(2S)-2- hydroxypropoxy]pyridin-2-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 414.3 371

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-[(3S)- oxolan-3-yl]acetamide 384.2 372

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](mehtyl)amino}-N-[(3R)- oxolan-3-yl]acetamide 384.2 373

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(oxetan-3- yl)acetamide 370.2 374

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(oxetan-3- yl)acetamide400.2 375

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-1-{5-methoxy-1H,2H,3H-pyrrolo[2,3-c]pyridin- 1-yl}ethan-1-one 477.2 376

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(1-methylcyclobutyl)acetamide 412.3 377

2-[(2-{4-[(2R)-2- hydroxypropoxy]pyridin-2-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(1-methylcyclobutyl)acetamide 426.3 378

2-[(2-{4-[(2S)-2- hydroxypropoxy]pyridin-2-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(1-methylcyclobutyl)acetamide 426.3 379

N-[(4-benzyl-1,3-oxazol-2- yl)methyl]-2-(4-methoxypyridin-2-yl)-N-methyl-5H,6H,7H- cyclopenta[d]pyrimidin-4-amine 428.2 380

2-(4-methoxypyridin-2-yl)-N- methyl-N-[(4-phenyl-1,3-oxazol-2-yl)methyl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-amine 414.2 381

N-tert-butyl-2-[(2-{4-[(1- hydroxycyclopentyl)methoxy]pyri-din-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide454.3 382

2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-1-(piperidin-1-yl)ethan-1-one 440.3 383

N-{bicyclo[1.1.1]pentan-1-yl}-2- ({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide 438.2 384

N-tert-butyl-2-{[2-(4-{[(2R)-1- hydroxypropan-2-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide414.3 385

N-tert-butyl-2-{[2-(4-{[(2S)-1- hydroxypropan-2-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide414.3 386

N-tert-butyl-2-[(2-{4-[(2S)-2- hydroxy-3-methylbutoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide442.3 387

N-tert-butyl-2-[(2-{4-[(2R)-2- hydroxy-3-methylbutoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide442.3 388

N-tert-butyl-2-[(2-{4-[(1- hydroxycyclobutyl)methoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide440.3 389

2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(propan-2- yl)acetamide414.3 390

N-ethyl-2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 400.2 391

1-(4,4-difluoropiperidin-1-yl)-2- ({2-[4-(2-hydroxy-2-methylproopoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl}(methyl)amino)ethan-1-one 476.3 392

2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(3-methylpentan-3-yl)acetamide 428.3 393

N-tert-butyl-2-[(2-{4-[(2R)-2- hydroxybutoxy]pyridin-2-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 428.3 394

N-tert-butyl-2-[(2-{4-[(2S)-2- hydroxybutoxy]pyridin-2-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 428.3 395

N-tert-butyl-2-({2-[4-(2-ethyl-2- hydroxybutoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 456.3 396

N-tert-butyl-2-[(2-{4-[(1- hydroxycyclohexyl)methoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide468.3 397

2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-[(1R,2S)-2-hydroxycyclopentyl]acetamide 456.3 398

N-cyclopropyl-2-({2-[4-(2- hydroxy-2- methylpropoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 412.3 399

2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-1-(morpholin-4-yl)ethan-1-one 442.3 400

N-tert-butyl-2-[(2-{4-[2- (diethylamino)ethoxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 455.4 401

N-tert-butyl-2-[methyl(2-{4-[2- (pyrrolidin-1-yl)ethoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide 453.4 402

N-tert-butyl-2-{[2-(4-{[(2S)-1- (dimethylamino)propan-2-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 441.3 403

2-{[2-(4-{[(tert- butylcarbamoyl)methyl](methyl)a- mino}-5H,6H,7H-cyclopenta[d]pyrimidin-2- yl)pyridin-4-yl]oxy}-N,N- dimethylacetamide441.3 404

N-tert-butyl-2-[(2-{4-[2- (dimethylamino)-2-methylpropoxy]pyridin-2-yl}- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide 455.4 405

N-tert-butyl-2-[(2-{4-[(4- hydroxyoxan-4- yl)methoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 470.3 406

N-tert-butyl-2-{[2-(4-{[(2R)-1- (dimethylamino)propan-2-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 441.3 407

N-tert-butyl-2-{[2-(4-{[1- (dimethylamino)-2-methylpropan-2-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 455.4 408

(2R)-N-tert-butyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]propanamide441.3 409

N-tert-butyl-2-({2-[4-(2-hydroxy- 2-methylpropoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}amino)acetamide 414.3 410

N-(1-cyclopropyl-1H-pyrazol-4- yl)-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2- yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide 477.3 411

N-tert-butyl-2-{methyl[2-(4- {[(2R)-1-methylpyrrolidin-2-yl]methoxy}pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide 453.4 412

N-tert-butyl-2-{methyl[2-(4- {[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide 453.4 413

N-tert-butyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2-yl}-5,5-dimethyl-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide 455.3 414

N-tert-butyl-2-{[2-(4-{[(4R)-2,2- dimethyl-1,3-dioxolan-4-yl]methoxy}pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimdin-4-yl](methyl)amino}acetamide 470.2 415

N-tert-butyl-2-[(2-{4-[(2R)-2,3- dihydroxypropoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 430.1 416

N-tert-butyl-2-[methyl(2-{4-[(1- methylazetidin1-3-yl)oxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide 425.3 417

2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-1-(pyrrolidin-1-yl)ethan-1-one 425.3 418

2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-[1-(trifluoromethyl)cyclopropyl]aceta- mide 479.3 419

N-tert-butyl-2-[methyl(2-{4-[2- (methylamino)ethoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide 413.3 420

2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-1-(pyrrolidin-1-yl)ethan-1-one 426.3 421

N-cyclopentyl-2-({2-[4-(2- hydroxy-2- methylpropoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 440.3 422

2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-[(3R)-oxolan-3-yl]acetamide 442.3 423

2-[(2-{4-[2-(dimethylamino)-2- methylpropoxy]pyridin-2-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N[1-(trifluoromethyl)cyclopropyl]aceta- mide 507.3 424

2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-[(3R)-oxolan-3-yl]acetamide 441.2 425

N-tert-butyl-2-[(2-{4-[(1-hydroxy- 2-methylpropan-2-yl)oxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide428.1 426

N-tert-butyl-2-[methyl({2-[4- (3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl})amino]acetamide 468.1 427

N-tert-butyl-2-({2-[4-(2- hydroxyethoxy)-6-methylpyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide414.3 428

2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(propan-2- yl)acetamide413.3 429

2-[methyl(2-{4-[2-(pyrrolidi-1- yl)ethoxy]pyridin-2-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]-N-(propan-2- yl)acetamide 439.3 430

2-[methyl(2-{4-[2-(morpholin-4- yl)ethoxy]pyridin-2-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]-N-(propan-2- yl)acetamide 455.3 431

2-[2-{4-[(1- hydroxycyclopropyl)methoxy]pyri- din-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(propan-2- y)acetamide412.3 432

2-[methyl(2-{4-[2-(4- methylpiperazin-1- yl)ethoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]-N-(propan-2- yl)acetamide468.3 433

(2R)-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(propan-2- yl)propanamide427.3 434

(2S)-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(propan-2- yl)propanmide427.3 435

2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-5,5-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(propan-2- yl)acetamide441.3 436

2-[methyl(2-{4-[2-(3- oxomorpholin-4- yl)ethoxy]pyridin-2-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]-N-(propan-2- yl)acetamide 469.3 437

N-tert-butyl-2-{methyl[2-(4- {[(3R)-1-methylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide 439.3 438

N-tert-butyl-2-{methyl[2-(4- {[(3S)-1-methylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide 439.4 440

N-tert-butyl-2-({2-[4-(2-hydroxy- 2-methylpropoxy)-6-methylpyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide 442.3 441

N-ethyl-2-[(2-{4-[(1- hydroxycyclopropyl)methoxy]pyri-din-2-l}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide398.2 442

N-ethyl-2-({2-[4-(2-ethyl-2- hydroxybutoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 428.3 443

2-({2-[4-(2-ethyl-2- hydroxybutoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N- methylacetamide 414.3 444

2-[(2-{4-[(4-hydroxyoxan-4- yl)methoxy]pyridin-2-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(propan-2- yl)acetamide456.3 445

N-tert-butyl-2-[(2-{4-[(2R)-2- hydroxy-2-methylbutoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide442.3 446

N-tert-butyl-2-[(2-{4-[(2S)-2- hydroxy-2-methylbutoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide442.3 447

N-ethyl-2-[(2-{4-[(4- hydroxyoxan-4- yl)methoxy]pyridin-2-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 442.3 448

2-[(2-{4-[(2R)-2-hydroxy-3- methoxypropoxy]pyridin-2-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(propan-2- yl)acetamide430.2 449

2-({2-[4-(2-hydroxy-2- mehtylpropoxy)pyridin-2-yl]-6,6-dimethyl-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(propan-2- yl)acetamide 442.3 450

2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]-7,7-dimethyl-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(propan-2- yl)acetamide 442.3 451

N-tert-butyl-2-[(2-{4-[(2S)-2,3- dihydroxypropoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimdiin-4- yl)(methyl)amino]acetamide 430.2 452

N-tert-butyl-2-[(2-{4-[(2S)-3- fluoro-2-hydroxypropoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide432.1 453

(2R)-2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(propan-2- yl)propanamide428.3 454

N-tert-butyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2-yl}-6,6-dimethyl-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide 455.3 455

2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-6,6-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(propan-2- yl)acetamide441.3 456

2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-7,7-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(propan-2- yl)acetamide441.3 457

N-tert-butyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2-yl}-7,7-dimethyl-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide 455.3 458

N-[(2R)-1-hydroxypropan-2-yl]-2- {[2-(4-methoxypyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 372.2 459

N-[(2S)-1-hydroxypropan-2-yl]-2- {[2-(4-methoxypyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 372.2 460

N-tert-butyl-2-[methyl(2-{4-[2- (morpholin-4-yl)ethoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide 469.3 461

N-tert-butyl-2-{methyl[2-(4-{2- [(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5- yl]ethoxy}pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 481.3 462

N-tert-butyl-2-{methyl[2-(4-{2- [(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5- yl]ethoxy}pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide 481.3 463

N-tert-butyl-2-{[2-(4-{2-[(3R)-3- methoxypyrrolidin-1-yl]ethoxy}pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 483.3 464

N-tert-butyl-2-{[2-(4-{2-[(3S)-3- methoxypyrrolidin-1-yl]ethoxy}pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 483.3 465

N-tert-butyl-2-[(2-{4-[2-(1H- imidazol-1-yl)ethoxy]pyridin-2-yl)}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide450.2 466

N-tert-butyl-2-[methyl(2-{4-[2- (1H-1,2,3,4-tetrazol-1-yl)ethoxy]pyridin-2-yl}- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)amino]acetamide 452.2 467

N-tert-butyl-2-{[2-(4- ethoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 384.2 468

N-tert-butyl-2-[methyl(2-{4-[2- (pyridazin-3-yloxy)ethoxy]pyridin-2-yl}- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)amino]acetamide 478.2 469

2-({2-[4-(2-ethyl-2- hydroxybutoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-[(1R,2S)-2-hydroxycyclopentyl]acetamide 484.3 470

N-tert-btuyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(2,2,2- trifluoroethyl)amino]acetamide495.3 471

1-[(3R)-3-hydroxypyrrolidin-1- yl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl](methyl)amino}ethan-1-one384.2 472

1-[(3S)-3-hydroxypyrrolidin-1-yl]- 2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl](methyl)amino}ethan-1-one 384.2473

N-tert-butyl-2-{[2-(4-{2-[(3R)-3- fluoropyrrolidin-1-yl]ethoxy}pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 471.2 474

N-tert-butyl-2-{[2-(4-{2-[(3S)-3- fluoropyrrolidin-1-yl]ethoxy}pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 471.2 475

N-tert-butyl-2-[(2-{4-[3- (dimethylamino)propyl]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 425.3 476

N-[2-(dimethylamino)ethyl]-2- {[2-(4-methoxypyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 385.2 477

2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-1-(morpholin- 4-yl)ethan-1-one 384.2 478

2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino]-N-(2,2,2-trifluoroethyl)acetamide 453.2 479

2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(2,2,2-trifluoroethyl)acetamide 454.1 480

N-tert-butyl-2-[methyl(2-{4-[3- (methylamino)propyl]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimdin-4- yl)amino]acetamide 411.3 481

N-tert-butyl-2-({2-[4-(3-hydroxy- 3-methylbutyl)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 426.3 482

N-tert-butyl-2-{[2-(4- hydroxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide 356.2 483

2-({2-[4-(2-aminoethoxy)pyridin- 2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-tert- butylacetamide 399.3484

N-tert-butyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]acetamide 413.3 485

N-tert-butyl-2-[2-{4-[2- (methylamino)ethoxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]acetamide 399.2 486

2-{[2-(4-{[(2R)-1- (dimethyamino)propan-2-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-[1- (trifluoromethyl)cyclopropyl]aceta- mide 493.3487

2-{methyl[2-(4-{[(3R)-1- methylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl]amino}-N-[1-(trifluoromethyl)cyclopropyl]aceta- mide 491.3 488

N-tert-butyl-2-{[2-(4-{[(3R,5R)- 1,5-dimethylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 453.3 489

N-tert-butyl-2-{methyl[2-(4- {[(3R)-1-methylpiperidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide 453.3 490

N-tert-butyl-2-{methyl[2-(4- {[(3S)-1-methylpiperidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide 453.3 491

N-tert-butyl-2-{[2-(4-{[(3R)-1- (2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 489.3 492

N-tert-butyl-2-({2-[4-(2-hydroxy- 2-methylpropoxy)pyridin-2-yl]-5-oxo-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 442.2493

N-tert-butyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2-yl}-5-hydroxy-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide 443.2 494

N-tert-butyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2-yl}-7-hydroxy-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide 443.3 495

N-tert-butyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2- yl}-5H,6H,7H-cyclopenta[b]pyridin-4- yl)(methyl)amino]acetamide 426.3 496

N-tert-butyl-2-{[2-(4-{[(3R)-1- ethylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide453.3 497

N-tert-butyl-2-{[2-(4-{[(3R)-1-(2- fluoroethyl)pyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 471.3 498

N-tert-butyl-2-[methyl({2-[4- (methylsulfanyl)pyridin-2-yl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl})amino]acetamide 386.2 499

N-tert-butyl-2-{[2-(4-{[2- (dimethylamino)ethyl]sulfanyl}py-ridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 443.3 500

N-cyclopropyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)(methyl)amino]acetamide 411.3501

N-tert-butyl-2-({2-[4-(2-hydroxy- 2-methylpropoxy)pyridin-2-yl]-7-oxo-5H,6H,7H- cyclopenta[d]pyrimdin-4- yl}(methyl)amino)acetamide 442.3502

N-tert-butyl-2-{[2-(4-{[(3R,5S)- 1,5-dimethylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide 453.4 503

(2R)-N-tert-butyl-2-{methyl[2-(4- {[(3R)-1-methylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}propanamide 453.4 504

(2R)-2-{methyl[2-(4-{[(3R)-1- methylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}-N-(propan-2- yl)propanamide 439.3 505

2-[methyl(2-{4-[2-(thiomorpholin- 4-yl)ethoxy]pyridin-2-yl}- 5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]-N-(propan-2- yl)acetamide 471.3 506

N-tert-butyl-2-[methyl(2-{4-[2- (methylsulfanyl)ethoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl)amino]acetamide 430.2 507

N-tert-butyl-2-({2-[4-(2- methanesulfonylethoxy)pyridin-2- yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide 462.3 508

N-tert-butyl-2-{[2-(4-{2- [di(2H3)methylamino]ethoxy}pyri-din-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide433.3 509

N-tert-butyl-2-({2-[4-(2-hydroxy- 2-methylpropoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}((2H3)methyl)amino)acetamide 431

III. Pharmaceutical Compositions and Modes of Administration

Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provided herein are alsopharmaceutical compositions that comprise one or more of the compoundsdescribed herein or a pharmaceutically acceptable salt, a stereoisomer,or a mixture of stereoisomers thereof and one or more pharmaceuticallyacceptable vehicles selected from carriers, adjuvants and excipients.Suitable pharmaceutically acceptable vehicles may include, for example,inert solid diluents and fillers, diluents, including sterile aqueoussolution and various organic solvents, permeation enhancers,solubilizers and adjuvants. Such compositions are prepared in a mannerwell known in the pharmaceutical art. See, e.g., Remington'sPharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed.(1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S.Banker & C. T. Rhodes, Eds.).

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical composition may be administered byvarious methods including, for example, rectal, buccal, intranasal andtransdermal routes. In certain embodiments, the pharmaceuticalcomposition may be administered by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of thecompounds described herein. Administration may be via, for example,capsule or enteric coated tablets. In making the pharmaceuticalcompositions that include at least one compound described herein or apharmaceutically acceptable salt, a stereoisomer, or a mixture ofstereoisomers thereof, the active ingredient is usually diluted by anexcipient and/or enclosed within such a carrier that can be in the formof a capsule, sachet, paper or other container. When the excipientserves as a diluent, it can be in the form of a solid, semi-solid, orliquid material, which acts as a vehicle, carrier or medium for theactive ingredient. Thus, the compositions can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, suspensions,emulsions, solutions, syrups, aerosols (as a solid or in a liquidmedium), ointments containing, for example, up to 10% by weight of theactive compound, soft and hard gelatin capsules, sterile injectablesolutions, and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions that include at least one compound described herein ora pharmaceutically acceptable salt, a stereoisomer, or a mixture ofstereoisomers thereof can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the subject by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methodsdisclosed herein employ transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds described herein in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein or a pharmaceutically acceptable salt, astereoisomer, or a mixture of stereoisomers thereof. When referring tothese preformulation compositions as homogeneous, the active ingredientmay be dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation may include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedherein. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect. In otherembodiments, compositions in pharmaceutically acceptable solvents may benebulized by use of inert gases. Nebulized solutions may be inhaleddirectly from the nebulizing device or the nebulizing device may beattached to a facemask tent, or intermittent positive pressure breathingmachine. Solution, suspension, or powder compositions may beadministered, preferably orally or nasally, from devices that deliverthe formulation in an appropriate manner.

The specific dose level of a compound of the present application for anyparticular subject will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease in the subject undergoing therapy. Forexample, a dosage may be expressed as a number of milligrams of acompound described herein per kilogram of the subject's body weight(mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate.In some embodiments, about 0.1 and 100 mg/kg may be appropriate. Inother embodiments a dosage of between 0.5 and 60 mg/kg may beappropriate. Normalizing according to the subject's body weight isparticularly useful when adjusting dosages between subjects of widelydisparate size, such as occurs when using the drug in both children andadult humans or when converting an effective dosage in a non-humansubject such as dog to a dosage suitable for a human subject. A dose maybe administered once a day (QID), twice per day (BID), or morefrequently, depending on the pharmacokinetic and pharmacodynamicproperties, including absorption, distribution, metabolism, andexcretion of the particular compound. In addition, toxicity factors mayinfluence the dosage and administration regimen. When administeredorally, the pill, capsule, or tablet may be ingested daily or lessfrequently for a specified period of time. The regimen may be repeatedfor a number of cycles of therapy.

IV. Methods of Treatment

In certain embodiments, the subject matter described herein is directedto a method of inhibiting iron transport mediated by ferroportin in asubject, comprising administering to a subject an effective amount of acompound of Formula I or Formula I′, or a pharmaceutically acceptablesalt thereof.

In certain embodiments, the subject matter described herein is directedto a method of treating a subject afflicted with a disease related to orcaused by reduced hepcidin levels, increased ferroportin levels, reducedsensitivity of ferroportin to hepcidin, increased iron levels, increasediron absorption, iron overload, increased erythropoiesis, stresserythropoiesis, or ineffective erythropoiesis, comprising administeringto the subject an effective amount of a compound of Formula I or FormulaI′.

In certain embodiments, the disease is related to or caused by reducedhepcidin levels, reduced sensitivity of ferroportin to hepcidin, ahemoglobinopathy, or iron overload.

In certain embodiments, the disease is related to or caused by reducedhepcidin levels or reduced sensitivity of ferroportin to hepcidin.

In certain embodiments, the disease is hemochromatosis.

In certain embodiments, the disease is related to or caused by ahemoglobinopathy.

In certain embodiments, the disease is thalassemia, hemoglobin Edisease, hemoglobin H disease, or sickle cell disease.

In certain embodiments, the disease is sickle cell disease.

In certain embodiments, the sickle cell disease is sickle cell anemia.

The methods described herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods described herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. In this context, the compoundsand compositions described herein may be used for a variety of purposes,including therapeutic and experimental purposes. For example, thecompounds and compositions described herein may be used ex vivo todetermine the optimal schedule and/or dosing of administration of acompound of the present disclosure for a given indication, cell type,individual, and other parameters. Information gleaned from such use maybe used for experimental purposes or in the clinic to set protocols forin vivo treatment. Other ex vivo uses for which the compounds andcompositions described herein may be suited are described below or willbecome apparent to those skilled in the art. The selected compounds maybe further characterized to examine the safety or tolerance dosage inhuman or non-human subjects. Such properties may be examined usingcommonly known methods to those skilled in the art.

The ferroportin inhibition activity of the compounds of Formula I orFormula I′ and pharmaceutically acceptable salts thereof provide methodsparticularly suitable for the use in the inhibition of iron transportmediated by ferroportin. As such, the compounds of Formula I or FormulaI′ and pharmaceutically acceptable salts thereof are useful in theprophylaxis and/or treatment of a disease related to or caused byreduced hepcidin levels, increased ferroportin levels, reducedsensitivity of ferroportin to hepcidin, increased iron levels, increasediron absorption, iron overload, increased erythropoiesis, stresserythropoiesis, or ineffective erythropoiesis.

Further, the compounds of Formula I or Formula I′ are suitable for theuse in an adjunctive therapy by limiting the amount of iron available topathogenic microorganisms, e.g. the siderophilic bacteria Vibriovulnificus and Yersinia enterocolitica, and common pathogens (e.g.Escherichia coli), thereby preventing or treating infections,inflammation, sepsis, and septic shock caused by said pathogenicmicroorganisms.

In certain embodiments, the subject matter described herein is directedto a method of inhibiting iron transport mediated by ferroportin in asubject, comprising administering to the subject an effective amount ofa compound of Formula I or Formula I′ or a pharmaceutically acceptablesalt thereof.

In certain embodiments, the subject matter described herein is directedto a method of treating a subject afflicted with a disease related to orcaused by reduced hepcidin levels, increased ferroportin levels, reducedsensitivity of ferroportin to hepcidin, a hemoglobinopathy, increasediron levels, increased iron absorption, iron overload (e.g. due to bloodtransfusions), increased erythropoiesis, stress erythropoiesis, orineffective erythropoiesis, comprising administering to the subject aneffective amount of a compound of Formula I or Formula I′ or apharmaceutically acceptable salt thereof. In aspects of theseembodiments, the treating comprises inhibiting iron transport mediatedby ferroportin in the subject.

In certain embodiments, the subject matter described herein is directedto a method of treating a subject afflicted with a disease related to orcaused by reduced hepcidin levels, reduced sensitivity of ferroportin tohepcidin, a hemoglobinopathy, or iron overload.

In certain embodiments, the subject matter described herein is directedto a method of treating a subject afflicted with a disease related to orcaused by reduced hepcidin levels or reduced sensitivity of ferroportinto hepcidin. In a certain aspect of this embodiment, the disease ishemochromatosis.

In certain embodiments, the subject matter described herein is directedto a method of treating a subject afflicted with a disease related to orcaused by a hemoglobinopathy. In a certain aspects of this embodiment,the disease is thalassemia, hemoglobin E disease, hemoglobin H disease,or sickle cell disease. In certain aspects of this embodiment, thedisease is sickle cell disease. In certain aspect of this embodiment,the disease is sickle cell anemia.

In certain embodiments, the diseases being associated with, beingrelated to, being caused by or leading to increased iron levels,increased iron absorption, iron overload (e.g., tissue iron overload) orineffective erythropoiesis comprise thalassemia, hemoglobinopathy, suchas hemoglobin E disease (HbE), hemoglobin H disease (HbH),haemochromatosis, hemolytic anemia, such as sickle cell anemia andcongenital dyserythropoietic anemia. Additional diseases beingassociated with, being related to, being caused by or leading toincreased iron levels, increased iron absorption, iron overload (e.g.,tissue iron overload) include neurodegenerative diseases, such as forexample Alzheimer's disease, Parkinson's disease, Huntington's disease,multiple sclerosis, Wilson's disease, amyotrophic lateral sclerosis(ALS), and Friedreich's Ataxia, wherein the compounds and methods areconsidered to be effective by limiting the deposition or increase ofiron in tissue or cells; conditions associated with the formation ofradicals, reactive oxygen species (ROS) and oxidative stress caused byexcess iron or iron overload; cardiac, liver and endocrine damage causedby excess iron or iron overload; inflammation triggered by excess ironor iron overload; diseases associated with ineffective erythropoiesis,such as myelodysplastic syndromes (MDS, myelodysplasia), polycythemiavera, and congenital dyserythropoietic anemia; diseases, disordersand/or disease conditions that comprise iron overload caused bymutations in genes involved in sensing the systemic iron stores, such ashepcidin/hepcidin antimicrobial peptide (HAMP), hemochromatosis protein(HFE), hemojuvelin (HJV) and transferrin receptor 2 (TFR2), such as inparticular diseases related to HFE and HJV gene mutations; diseasesrelated to ferroportin mutations; chronic hemolysis associated diseases,sickle cell diseases (including sickle cell anemia (HbSS) as well ashemoglobin SC disease (HbSC), hemoglobin S beta-plus-thalassemia(HbS/β+), and hemoglobin S beta-zero-thalassemia (HbS/β0)), red cellmembrane disorders, Glucose-6-phosphate dehydrogenase deficiency (G6PDdeficiency), erythropoietic porphyria, Friedreich's Ataxia, as well assubgroups of iron overload such as transfusional iron overload, ironintoxication, pulmonary hemosiderosis, osteopenia, insulin resistance,African iron overload, Hallervordan Spatz disease, hyperferritinemia,ceruloplasmin deficiency, neonatal hemochromatosis and red blood celldisorders comprising thalassemia, including alpha thalassemia, betathalassemia and delta thalassemia, thalassemia intermedia, sickle celldisease and myelodyplastic syndrome; liver diseases (e.g. hepatitis Bvirus infection, hepatitis C virus infection, alcoholic liver disease,autoimmune hepatitis), other conditions including ataxia, Friedreich'sataxia, age-related macular degeneration, age-related cataract,age-related retinal diseases and neurodegenerative disease, such aspantothenate kinase-associated neurodegeneration, restless leg syndromeand Huntington's disease. In certain embodiments, the disease is sicklecell anemia. The ferroportin inhibition activity, for instance byinducing internalization of ferroportin, of the compounds of Formula Iand pharmaceutically acceptable salts thereof can be determined by theassays described herein as well as those described in WO2018/192973,incorporated herein by reference in its entirety.

The activity of the compounds of Formula I or Formula I′ in thetreatment of sickle cell anemia (sickle cell disease) can be determinedby using a mouse model, such as e.g. described by Yulin Zhao et al. in“MEK1/2 inhibitors reverse acute vascular occlusion in mouse models ofsickle cell disease”; The FASEB Journal Vol. 30, No. 3, pp 1171-1186,2016. Said mouse model can be suitably adapted to determine the activityof the compounds of Formula I or Formula I′ in the treatment of sicklecell anemia. In certain embodiments, the disease is caused by a lack ofhepcidin or iron metabolism disorders, particularly iron overloadstates, such as thalassemia, sickle cell disease and hemochromatosis. Incertain embodiments, the disease is related to or caused by reducedhepcidin levels, increased iron levels, increased iron absorption, ironoverload, increased erythropoiesis, stress erythropoiesis, orineffective erythropoiesis. In certain embodiments, the disease isselected from the group consisting of thalassemia, hemoglobinopathy,hemoglobin E disease, hemoglobin H disease, haemochromatosis, andhemolytic anemia.

In certain embodiments, the methods of administering and treatingdescribed herein further comprise co-administration of one or moreadditional pharmaceutically active compounds or in combination with ablood transfusion.

In a combination therapy, the pharmaceutically active compounds can beadministered at the same time, in the same formulation, or at differenttimes. Such combination therapy comprises co-administration of acompound of Formula I or Formula I′ or a pharmaceutically acceptablesalt thereof with at least one additional pharmaceutically activecompound. Combination therapy in a fixed dose combination therapycomprises co-administration of a compound of Formula I or Formula I′ ora pharmaceutically acceptable salt thereof with at least one additionalpharmaceutically active compound in a fixed-dose formulation.Combination therapy in a free dose combination therapy comprisesco-administration of a compound of Formula I or Formula I′ or apharmaceutically acceptable salt thereof and at least one additionalpharmaceutically active compound in free doses of the respectivecompounds, either by simultaneous administration of the individualcompounds or by sequential use of the individual compounds over a periodof time.

The additional pharmaceutically active compound includes in particulardrugs for reducing iron overload (e.g., Tmprss6-ASO or siRNA) or ironchelators, in particular curcumin, SSP-004184, Deferitrin, deferasirox,deferoxamine and/or deferiprone, or antioxidants such as n-acetylcysteine, anti-diabetics such as GLP-1 receptor agonists, antibioticssuch as penicillin, vancomycin (Van) or tobramycin, antifungal drugs,anti-viral drugs such as interferon-a or ribavirin, drugs for thetreatment of malaria, anticancer agents, drugs for the treatment ofneurodegenerative diseases such as Alzheimer's disease and Parkinson'sdisease (e.g., dopamine agonists such as Levodopa), orimmunosuppressants (cyclosporine A or cyclosporine A derivatives), ironsupplements, vitamin supplements, red cell production stimulators (e.g.,erythropoietin, Epo), anti-inflammatory agents, anti-thrombolytics,statins, vasopressors and inotropic compounds. A further object of thepresent invention relates to the use of the above combinations for theprophylaxis and/or treatment of diseases caused by a lack of hepcidin oriron metabolism disorders, such as particularly iron overload statessuch as in particular thalassemia, sickle cell disease andhemochromatosis and other disorders as described in the presentapplication.

In certain embodiments, the subject matter described herein is directedto a method of treating beta-thalassemia (b-thalassemia) in a subject,comprising administering to the subject an effective amount of acompound of Formula I or a pharmaceutically acceptable salt thereof. Thecompounds of Formula I as defined herein, act as ferroportin inhibitorsand can be used for treating severe forms of b-thalassemia, such astransfusion-dependent b-thalassemia, including in particularb-thalassemia major and hemoglobin E b-thalassemia and the symptoms andpathological conditions associated therewith, such as in particulardefective red blood cell production in the bone marrow, ineffectiveerythropoiesis, low hemoglobin levels/anemia, multiple organdysfunction, iron overload, liver iron loading and cardiac ironoverload, paleness, fatigue, jaundice, and splenomegaly.

In particular, a severe form of b-thalassemia is transfusion-dependentb-thalassemia (TDT), including in particular b-thalassemia major andsevere forms of hemoglobin E b-thalassemia. Severe forms ofb-thalassemia and hemoglobin E 13-thalassemia, require that patientssuffering therefrom achieve regular blood transfusions/Red Blood Celltransfusions (RBC transfusions). Such severe forms of b-thalassemia arethus also summarized as transfUsion-dependent b-thalassemia (TDT). Thusthe methods of treating severe forms of b-thalassemia, such as inparticular transfusion-dependent b-thalassemia (TDT), include inparticular b-thalassemia major and severe forms of hemoglobin Eb-thalassemia by administering to a subject in need thereof one or moreof the compounds of Formula I as described herein.

The subject may be: suffering from b-thalassemia or haemoglobin Eb-thalassemia and requiring regular blood transfusion; suffering fromb-thalassemia major and/or severe haemoglobin E b-thalassemia, moreparticularly to patients suffering from b-thalassemia major.

The methods of treating beta-thalassemia can result in: reduced NTBIlevels in a subject; reduced LPI levels in a subject; reduced alphaglobin aggregate levels in a subject; reduced ROS levels in RBCs of asubject; a decrease in liver iron concentration in the subject; adecrease in myocardial iron concentration in the subject; an improvementof at least one of the parameters Hct, MCV, MCH, ROW and reticulocytenumbers in the subject; in an erythroid response, which comprises areduction in transfusion burden in the subject; a reduction oftransfusion burden in the subject compared to the transfusion burdenprior to treatment using the methods; achieving no longer requiring atransfusion in a transfusion-dependent b-thalassemia subject; reducedserum ferritin levels in the subject; a reduction of the symptomsassociated with one or more transfusion-dependent b-thalassemia clinicalcomplications. Nonlimiting examples of transfusion-dependentb-thalassemia symptoms include growth retardation, pallor, jaundice,poor musculature, genu valgum, hepatosplenomegaly, leg ulcers,development of masses from extramedullary hematopoiesis, skeletalchanges resulting from expansion of the bone marrow, and clinicalcomplications of chronic red blood cell transfusions, such as, forexample hepatitis B virus infection, hepatitis C virus infection andhuman immunodeficiency virus infection, alloimmunization, and organdamage due to iron overload, such as, for example, liver damage, heartdamage and endocrine gland damage. Although the compounds of the formula(I) are not expected to directly affect growth differentiation factor 11(GDF11), decrease of skeletal deformities can also occur caused byreduced extramedullary erythropoiesis.

The following parameters can be determined to evaluate the efficacy ofthe compounds of the present invention in the new medical use: serumiron, NTBI levels, LPI (Labile Plasma Iron) levels, erythropoietin, TSAT(transferrin saturation), Hb (hemoglobin), Hct (haematocrit), MCV (MeanCell Volume), MCH (Mean Cell Hemoglobin), RDW (Red Blood CellDistribution Width) and reticulocyte numbers, complete blood counts,spleen and liver weight, erythropoiesis in spleen and bone marrow,spleen and liver iron content and alpha-globin aggregates in RBCmembranes. The determination can be carried out using conventionalmethods of the art, in particular by those described below in moredetail. The compounds (I) of the present invention are suitable toimprove at least one of these parameters.

The methods can be prior to or accompanying blood transfusion to preventor at least attenuate occurrence of transfusion-caused pathologicalconditions.

In certain embodiments, the subject matter described herein is directedto a method of preventing and treating kidney injuries in a subject,comprising administering to the subject an effective amount of acompound of Formula I or a pharmaceutically acceptable salt thereof. Incertain aspects of these embodiments, the compound of Formula I can beco-administered with another pharmaceutically active compound. Incertain aspects of these embodiments, the kidney injuries are thoseinduced by catalytic free iron. In certain aspects of these embodiments,the kidney injuries are selected from renal ischemia-reperfusion injury(IRI), ischemic injury and acute kidney injuries. In a further aspect,kidney injuries are selected from acute kidney injury (AK!), renalischemia-reperfusion injury (IRI), ischemic injury and AKI caused byischemic injury, AKI following surgery or surgical intervention, such asin particular following cardiac surgery most often with proceduresinvolving cardiopulmonary bypass, other major chest or abdominalsurgery, and kidney injury associated with RBC transfusion.

The term “preventing” and the like includes the protection from ischemicrenal injury, avoidance of occurrence of AKI or at least reducing theseverity of AKI following ischemic injury, RBC transfusion or a surgeryintervention e.g. by administering the compounds prior to oraccompanying or shortly after an ischemic event, RBC transfusion or thesurgery intervention to prevent or at least attenuate occurrence ofkidney injuries induced by catalytic free iron.

Free catalytic iron or labile iron or NTBI is considered as a main causeof kidney injury, such as in particular AKI triggered by ischemia. Theadministration of the ferroportin inhibitor compounds of formula (I) asdescribed herein can protect against the damaging effects of catalyticfree iron. Without being bound to theory, the ferroportin inhibitorsdescribed herein can reduce or prevent the formation of catalytic freeiron or NTBI by sequestering iron in macrophages of liver and spleen,therewith reducing its levels in plasma and reducing the risk of ROSformation. The compounds of Formula I described herein act asferroportin inhibitors, and have the potential to sequester iron inmacrophages, thereby interrupting the cycle of self-sustaining releaseof catalytic free iron. The compounds of the Formula I are suitable forthe prevention and treatment of the kidney injuries described herein bylimiting reactive oxygen species (ROS) to avoid kidney tissue injury.Further to catalytic free iron, NTBI and LPI (Labile Plasma Iron) cancause kidney injuries. NTBI encompasses all forms of serum iron that arenot tightly associated with transferrin and is chemically andfunctionally heterogeneous. LPI represents a component of NTBI that isboth redox active and chelatable, capable of permeating into organs andinducing tissue iron overload.

The following parameters can be determined to evaluate the efficacy ofthe compounds for treating kidney injuries: plasma creatinine,glomerular filtration rate (including estimated glomerular filtrationrate eGFR), urine albumin excretion, urine neutrophilgelatinase-associated lipocalin (NGAL), NTBI, LPI, RBC hemolysis, bloodurea nitrogen (BUN), plasma hemoglobin (Hb), total plasma iron, plasmahepcidin, renal neutrophil infiltration, serum IL-6, spleen, kidneyand/or liver iron content, renal ferroportin, KIM-1 (Kidney InjuryMolecule-1) as an acute marker for kidney injury in blood and urine, andH-ferritin. Additionally or alternatively, the efficacy of the compoundsof the present invention can be determined via the kidney tubular injuryscore, such as e.g. the CSA-NGAL score (Cardiac Surgery Associated NGALScore) for detecting acute tubular damage as described in more detailbelow, the KDIGO score described in more detail below or the EGTI scorecomprising Endothelial, Glomerular, Tubular and Interstitial (EGTI)components to evaluate histology (described e. g, by: Khalid et al.‘Kidney ischaemia reperfusion injury in the rat the EGTI scoring systemas a valid and reliable tool for histological assessment” Journal ofHistology & Histopatholoy, Vol. 3, 2016).

The methods of treating or preventing kidney injury can result in adecrease of serum creatinine (sCr) in the subject. The methods oftreating or preventing kidney injury can result in a corrected(decreased) urine albumin excretion in the subject. The methods oftreating or preventing kidney injury can result in a decrease of bloodurea nitrogen (BUN) in the subject. The methods of treating orpreventing kidney injury can result in a decrease of total plasma ironin the subject. The methods of treating or preventing kidney injury canresult in a decrease of interleukin-6 (!L-6) levels in the subject. Themethods of treating or preventing kidney injury can result in a decreaseof KIM-1 levels in the subject. The methods of treating or preventingkidney injury can result in an increase in spleen and/or liver ironconcentration in the subject. The methods of treating or preventingkidney injury can result in a decrease in kidney iron concentration inthe subject. The methods of treating or preventing kidney injury canresult in reduced NTBI levels. The methods of treating or preventingkidney injury can result in reduced LPI levels in the subject. Themethods of treating or preventing kidney injury can result in aninhibition of tubular injury, such as tubular necrosis. The methods oftreating or preventing kidney injury can result in an inhibition ofapoptosis. The methods of treating or preventing kidney injury canresult in a reduced IRI-induced renal neutrophil infiltration. Themethods of treating or preventing kidney injury can result in reducedROS levels in kidney tissue of the subject. The methods of treating orpreventing kidney injury can result in corrected (increased) kidneyH-ferritin levels in the subject. In particular, the methods of treatingor preventing kidney injury can reduce the occurrence of AKI, renalischemia-reperfusion injury and AKI caused by ischemic injury, AKIfollowing surgery or surgical intervention, such as in particularfollowing cardiac surgery most often with procedures involvingcardiopulmonary bypass, other major chest or abdominal surgery, andkidney injury associated with RBC transfusion. The methods of treatingor preventing kidney injury can comprise a) decrease, accelerateddecrease or prevention of increase of serum creatinine; and/or b)increase or prevention of decrease of estimated glomerular filtrationrate (eGFR); and/or c) decrease or prevention of increase of renalferroportin; and/or d) increase or prevention of decrease of H-ferritinlevels; and/or e) decrease or prevention of increase of renal neutrophilinfiltration; and/or f) decrease or prevention of increase of serum IL-6levels.

V. Methods of Preparing Compounds of Formula I and PharmaceuticallyAcceptable Salts Thereof

Compounds can be synthesized by synthetic routes that include processesanalogous to those well-known in the chemical arts, particularly inlight of the description contained herein, and those for otherheterocycles described in: Comprehensive Heterocyclic Chemistry II,Editors Katritzky and Rees, Elsevier, 1997, e.g., Volume 3; LiebigsAnnalen der Chemie, (9):1910-16, (1985); Helvetica Chimica Acta,41:1052-60, (1958); Arzneimittel-Forschung, 40(12):1328-31, (1990), eachof which are expressly incorporated by reference. Starting materials aregenerally available from commercial sources such as Aldrich Chemicals(Milwaukee, Wis.) or are readily prepared using methods well known tothose skilled in the art (e.g., prepared by methods generally describedin Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-23, Wiley, N.Y. (1967-2006 ed.), or Beilsteins Handbuch derorganischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, includingsupplements (also available via the Beilstein online database). DTTrefers to dithiothreitol. DHAA refers to dehydroascorbic acid.

Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing compounds andnecessary reagents and intermediates are known in the art and include,for example, those described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wiley and Sons(1999); and L. Paquette, ed., Encyclopedia of Reagents for OrganicSynthesis, John Wiley and Sons (1995) and subsequent editions thereof.

Compounds may be prepared singly or as compound libraries comprising atleast 2, for example 5 to 1,000 compounds, or 10 to 100 compounds.Libraries of compounds of Formula I may be prepared by a combinatorial‘split and mix’ approach or by multiple parallel syntheses using eithersolution phase or solid phase chemistry, by procedures known to thoseskilled in the art. Thus, according to a further aspect, there isprovided a compound library comprising at least 2 compounds, orpharmaceutically acceptable salts thereof.

The subject matter described herein is directed to the followingembodiments.

1A. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein,

Z is N or CH;

R⁶, in each instance, is selected from the group consisting of halogen,hydroxy, C₁-C₃ alkoxy, C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃ alkyl,hydroxy-C₁-C₆ alkoxy, hydroxy-C₁-C₃-alkyl, cyano, C₃-C₇ cycloalkyl-C₁-C₃alkoxy, NR^(G)R^(H), halo-C₁-C₃ alkoxy, and C₃-C₆ cycloalkyl;

-   -   wherein R^(G) and R^(H) are each independently hydrogen or C₁-C₃        alkyl; or

two R⁶ groups, taken together with the atom to which each is attached,form a 5- or 6-membered heterocyclyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, or5- to 10-membered heteroaryl;

n is 0, 1, 2, or 3;

Y¹, Y², Y³, and Y⁴ are each independently selected from the groupconsisting of CH, N, NH, O, S, and C (when R⁶ is attached thereto),provided that 1 or 2 of Y¹, Y², Y³, and Y⁴ can be N, NH, O, or S;

f is 0 or 1;

p is 1 or 2;

R^(x), in each instance, is halogen, C₁-C₆ alkyl, C₁-C₃ alkoxy, hydroxy,or cyano;

m is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, C₁-C₃ alkyl,hydroxy-C₁-C₃ alkyl, cyclopropyl, and phenyl;

R⁴ is selected from the group consisting of:

-   -   i. (5- to 10-membered monocyclic or bicyclic fused        heteroaryl)-C₁-C₃ alkyl branched or linear, or (6- or 7-membered        monocyclic heterocyclyl)-C₁-C₃ alkyl branched or linear;    -   wherein,        -   when p is 1, C₁-C₃ alkyl in the (5- to 10-membered            monocyclic or bicyclic fused heteroaryl)-C₁-C₃ alkyl is            linear;

and,

-   -   ii.

-   -   wherein,        -   R^(4a) and R^(4g) are each independently selected from the            group consisting of hydrogen, C₁-C₆ alkyl, hydroxy-C₁-C₆            alkyl, C₁-C₃ alkoxy-C₁-C₆ alkyl, C₃-C₇ cycloalkyl, 5- to            10-membered monocyclic, bicyclic fused, or spiro            heterocyclyl, C₆-C₁₀ aryl, 5- to 10-membered monocyclic or            bicyclic fused heteroaryl, (C₆-C₁₀ aryl)-C₁-C₃ alkyl, and            (5- to 10-membered monocyclic heteroaryl)-C₁-C₃ alkyl;            -   wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl,                arylalkyl, or heteroaryl-alkyl of R^(4a) or R^(4g) is                optionally substituted with one, two, or three                substituents, each independently selected from the group                consisting of halogen, C₁-C₆ alkyl, haloalkyl, hydroxy,                C₁-C₃ alkoxy, oxo, C₃-C₇ cycloalkyl, and 5- to                10-membered monocyclic, bicyclic fused, or spiro                heterocyclyl;        -   R^(4b) is hydrogen or C₁-C₆ alkyl; or        -   R^(4a) and R^(4b) taken together with the atom to which each            is attached form a 5- to 7-membered heterocyclyl; or        -   R^(4b) and R^(4c) taken together with the atom to which each            is attached form a 5- to 7-membered heterocyclyl optionally            substituted with one, two, or three substituents, each            independently selected from the group consisting of hydroxy,            halo, and C₁-C₃ alkyl; or        -   R^(4c) and R^(4d) are each independently selected from the            group consisting of hydrogen, C₁-C₃ alkoxy, hydroxy, C₁-C₃            alkyl-thio-C₁-C₃ alkyl, hydroxy-C₁-C₆ alkyl, C₁-C₆            alkoxy-C₁-C₃ alkyl, C₃-C₇ cycloalkyl, and C₁-C₃ alkyl; or        -   R^(4c) and R^(4d) taken together with the atom to which each            is attached form a C₃-C₇ cycloalkyl;

or, when p is 1,

-   -   R³ and R⁴ taken together with the nitrogen atom to which each is        attached can form a:        -   i. 7-membered bicyclic fused heterocyclyl, 7-membered            bridged heterocyclyl, or 7-membered monocyclic heterocyclyl            containing one or two heteroatoms;            -   wherein when said 7-membered monocyclic heterocyclyl                contains one heteroatom, said heterocyclyl is optionally                substituted with one, two, or three substituents, each                independently selected from the group consisting of oxo,                halogen, hydroxy, C₁-C₃ alkoxy, cyano, and C₁-C₃ alkyl;                and,            -   when said 7-membered monocyclic heterocyclyl contains                two heteroatoms, said heteroatoms are each independently                N or O, and said heterocyclyl is optionally substituted                with one, two, or three substituents, each independently                selected from the group consisting of C₁-C₃ alkyl,                cyano, oxo, halogen, haloalkyl, and C₆-C₁₀ aryl; and                -   wherein said aryl is optionally substituted with one                    or two substituents, each individually selected from                    the group consisting of C₁-C₃ alkoxy, hydroxy,                    halogen, and C₁-C₃ alkyl;        -   ii. 4- or 6-membered monocyclic heterocyclyl containing one            heteroatom;            -   wherein said 4-membered monocyclic heterocyclyl is                optionally substituted with one or two substituents,                each independently selected from the group consisting of                halogen, C₁-C₃ alkoxy, oxo, and                —(CH₂)_(s)C(═O)NR^(k)R^(l);                -   wherein, s is 0, 1, 2, or 3;                -   R^(k) is hydrogen or C₁-C₃ alkyl; and                -   R^(l) is selected from the group consisting of                    hydrogen, hydroxy, C₁—C₃ alkyl, C₃-C₇ cycloalkyl,                    and C₆-C₁₀ aryl;            -   wherein said 6-membered monocyclic heterocyclyl is                optionally substituted with one or two substituents,                each independently selected from the group consisting of                C₁-C₃ alkoxy, oxo, halogen, cyano, and NR^(q)R^(w);                -   wherein R^(q) is hydrogen or C₁-C₃ alkyl, and R^(w)                    is C₆-C₁₀ aryl or C₃-C₇ cycloalkyl, wherein said                    aryl or cycloalkyl is optionally substituted with                    one or two substituents, each independently selected                    from the group consisting of halogen, C₁-C₃ alkyl,                    hydroxy, and C₁-C₃ alkoxy;    -   or;        -   iii. 8-, 9-, 10- or 11-membered bicyclic fused heterocyclyl,            or 12-membered bicyclic bridged, fused heterocyclyl, wherein            said 8-, 9-, or 11-membered heterocyclyl contains one            heteroatom and said 10- or 12-membered heterocyclyl contains            one or two heteroatoms; and wherein said 10-, 11-, or            12-membered heterocyclyl is optionally substituted with one,            two, or three substituents, each independently selected from            the group consisting of halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy,            and hydroxy;

or, when p is 2,

-   -   R³ and R⁴ taken together with the nitrogen atom to which each is        attached can form a:        -   i. 6-membered monocyclic heterocyclyl containing one            heteroatom, optionally with one or two substituents, each            independently selected from the group consisting of halogen,            hydroxy-(C₁-C₆ alkyl), hydroxy, oxo, and C₁-C₃ alkoxy; or        -   ii. 4- or 7-membered monocyclic heterocyclyl containing one            or two heteroatoms, or 7-, 8-, 9, 10-, or 11-membered            bicyclic bridged, fused, or spiro heterocyclyl containing            one, two, or three heteroatoms, optionally substituted with            one or two substituents, each independently selected from            the group consisting of halogen, oxo, cyano, C₁-C₃ alkyl,            hydroxy, NR^(G)R^(H), and —(CH₂)_(s)C(═O)NR^(k)R^(l);

provided that when the structure of Formula (I) is

* is

and ** is

; or

* is

and ** is

;

and,

wherein the compound of Formula (I) is not:

-   N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine;-   4-(piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;-   4-(azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;-   1-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one;    or-   2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane;    or a salt thereof.    2A. The compound of embodiment 1A,    wherein,

Z is N;

R⁶, in each instance, is selected from the group consisting of halogen,hydroxy, C₁-C₃ alkoxy, C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃ alkyl,hydroxy-C₁-C₆ alkoxy, hydroxy-C₁-C₃-alkyl, and NR^(G)R^(H);

-   -   wherein R^(G) and R^(H) are each independently hydrogen or C₁-C₃        alkyl; or

wherein two R⁶ groups, taken together with the atom to which each isattached, form a 5- or 6-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to10-membered heteroaryl;

n is 0, 1, or 2;

Y¹, Y², Y³, and Y⁴ are each independently selected from the groupconsisting of CH, N, NH, and C (when R⁶ is attached thereto), providedthat 1 or 2 of Y¹, Y², Y³, and Y⁴ can be N or NH;

f is 0 or 1;

p is 1 or 2;

m is 0;

R³ is selected from the group consisting of hydrogen, C₁-C₃ alkyl, andhydroxy-C₁-C₃-alkyl;

R⁴ is selected from the group consisting of:

-   -   i. (5- to 10-membered monocyclic or bicyclic fused        heteroaryl)-C₁-C₃ alkyl branched or linear;        -   wherein,            -   when p is 1, C₁-C₃ alkyl in the (5- to 10-membered                monocyclic or bicyclic fused heteroaryl)-C₁-C₃ alkyl is                linear;    -   and,    -   ii.

-   -   -   wherein,            -   R^(4a) is selected from the group consisting of C₁-C₆                alkyl, hydroxy-C₁-C₆ alkyl, C₁-C₃ alkoxy-C₁-C₆ alkyl,                C₃-C₇ cycloalkyl, 5- to 10-membered monocyclic                heterocyclyl, C₆-C₁₀ aryl, 5- to 10-membered monocyclic                or bicyclic fused heteroaryl, (C₆-C₁₀ aryl)-C₁-C₃ alkyl,                and (5- to 10-membered monocyclic heteroaryl)-C₁-C₃                alkyl;                -   wherein the cycloalkyl, heterocyclyl, aryl,                    heteroaryl, arylalkyl, or heteroaryl-alkyl of R^(4a)                    is optionally substituted with one or two                    substituents, each independently selected from the                    group consisting of halogen, C₁-C₆ alkyl, haloalkyl,                    hydroxy, C₁-C₃ alkoxy, oxo, C₃-C₇ cycloalkyl, and 5-                    to 10-membered monocyclic, bicyclic fused, or spiro                    heterocyclyl;            -   R^(4g) is selected from the group consisting of C₆-C₁₀                aryl and C₁-C₃ alkyl;            -   R^(4b) is hydrogen or C₁-C₆ alkyl;            -   or, R^(4a) and R^(4b) taken together with the atom to                which each is attached form a 5- to 7-membered                heterocyclyl;            -   or, R^(4b) and R^(4c) taken together with the atom to                which each is attached form a 5- to 7-membered                heterocyclyl optionally substituted with one or two                substituents, each independently selected from C₁-C₃                alkyl;            -   R^(4c) and R^(4d) are each independently hydrogen or                C₁-C₃ alkyl;            -   or, R^(4c) and R^(4d) taken together with the atom to                which each is attached form a C₃-C₅ cycloalkyl;

or,

R³ and R⁴ taken together with the nitrogen atom to which each isattached form a:

-   -   i. 7-membered monocyclic heterocyclyl containing one or two        heteroatoms;        -   wherein when said 7-membered monocyclic heterocyclyl            contains one heteroatom, said heterocyclyl is optionally            substituted with one, two, or three substituents, each            independently selected from the group consisting of oxo,            halogen, hydroxy, C₁-C₃ alkoxy, cyano, and C₁-C₃ alkyl; and        -   when said 7-membered monocyclic heterocyclyl contains two            heteroatoms, said heteroatoms are each independently N or O,            and said heterocyclyl is optionally substituted with one,            two, or three substituents, each independently selected from            the group consisting of C₁-C₃ alkyl, cyano, oxo, halogen,            haloalkyl, and C₆-C₁₀ aryl; and            -   wherein said aryl is optionally substituted with one or                two substituents, each individually selected from the                group consisting of C₁-C₃ alkoxy, hydroxy, halogen, and                C₁-C₃ alkyl;    -   ii. 4- or 6-membered monocyclic heterocyclyl containing one        heteroatom;        -   wherein said 4-membered monocyclic heterocyclyl is            optionally substituted with —(CH₂)_(s)C(═O)NR^(k)R^(l);            -   wherein s is 0, 1, or 2;                -   R^(k) is hydrogen or C₁-C₃ alkyl; and                -   R^(l) is selected from the group consisting of                    hydrogen, methyl, phenyl, cyclopentyl, and                    cyclohexyl;        -   wherein said 6-membered monocyclic heterocyclyl is            optionally substituted with one or two substituents, each            independently selected from the group consisting of C₁-C₃            alkoxy, oxo, halogen, cyano, and NR^(q)R^(w);            -   wherein R^(q) is hydrogen or C₁-C₃ alkyl and R^(w) is                C₆-C₁₀ aryl or C₃-C₇ cycloalkyl, wherein said aryl or                cycloalkyl is optionally substituted with one or two                substituents, each independently selected from the group                consisting of halogen, C₁-C₃ alkyl, hydroxy, and C₁-C₃                alkoxy; or    -   iii. 10- or 11-membered bicyclic fused heterocyclyl containing        one heteroatom, optionally substituted with one, two, or three        substituents, each independently selected from the group        consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxy, and halogen.        3A. The compound of embodiment 1A or 2A, wherein Y¹, Y², Y³, and        Y⁴ are each CH or C (to which R⁶ is bound).        4A. The compound of embodiment 1A or 2A, wherein Y³ is N and Y¹,        Y², and Y⁴ are each CH or C (to which R⁶ is bound).        5A. The compound of embodiment 1A or 2A, wherein Y² is N and Y¹,        Y³, Y⁴ are each CH or C (to which R⁶ is bound).        6A. The compound of embodiment 1A or 2A, wherein Y¹ is N and Y²,        Y³, and Y⁴ are each CH or C (to which R⁶ is bound).        7A. The compound of any one of embodiments 1A-6A, wherein R⁶, in        each instance, is selected from the group consisting of halogen,        hydroxy, C₁-C₃ alkoxy, C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃ alkyl,        hydroxy-C₁-C₃ alkoxy, hydroxy-C₁-C₃-alkyl, and NR^(G)R^(H);

wherein R^(G) and R^(H) are each independently hydrogen or C₁-C₃ alkyl.

8A. The compound of embodiment 7A, wherein R⁶, in each instance, isselected from the group consisting of methoxy, methyl, fluoro, chloro,ethyl, N(CH₃)₂, hydroxy, —OCH₂CH₂OH, —CH₂OH, —CH₂OCH₃, and —CH₂CH₂OH.

9A. The compound of embodiment 8A, wherein R⁶, in each instance, ismethoxy or methyl.

10A. The compound of any one of embodiments 1A-6A, wherein two R⁶groups, taken together with the atom to which each is attached, form a5- or 6-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10-memberedheteroaryl.

11A. The compound of embodiment 10A, wherein two R⁶ groups, takentogether with the atom to which each is attached, form a pyrazolyl,dioxanyl, pyridinyl, or phenyl ring.

12A. The compound of any one of embodiments 1A-11A, wherein n is 1.

13A. The compound of any one of embodiments 1A-11A, wherein n is 0.

14A. The compound of any one of embodiments 1A-13A, wherein f is 1.

15A. The compound of any one of embodiments 1A-13A, wherein f is 0.

16A. The compound of any one of embodiments 1A-15A, wherein R³ isselected from the group consisting of hydrogen, methyl, and —CH₂CH₂OH.

17A. The compound of embodiment 16A, wherein R³ is methyl.

18A. The compound of any one of embodiments 1A-17A, wherein R⁴ is a (5-to 10-membered monocyclic or bicyclic fused heteroaryl)-methyl.

19A. The compound of embodiment 18A, wherein R⁴ is a (5- to 10-memberedmonocyclic or bicyclic fused heteroaryl)-methyl, wherein at least one ofthe ring atoms ortho to the attachment point is a nitrogen or oxygen.

20A. The compound of embodiment 18A or 19A, wherein R⁴ is selected fromthe group consisting of pyridinyl-methyl, pyrimidinyl-methyl, andbenzoxazole-methyl.

21A. The compound of any one of embodiments 1A-17A, wherein, wherein R⁴is

22A. The compound of embodiment 21A, wherein R^(4c) and R^(4d) are eachindependently hydrogen or methyl.23A. The compound of embodiment 22A, wherein R^(4c) and R^(4d) are eachhydrogen.24A. The compound of any one of embodiments 21A-23A, wherein R^(4b) ishydrogen.25A. The compound of any one of embodiments 21A-24A, wherein R^(4a) isC₁-C₆ alkyl.26A. The compound of embodiment 25A, wherein R^(4a) is tert-butyl.27A. The compound of any one of embodiments 21A-24A, wherein R^(4a) isC₆-C₁₀ aryl optionally substituted with one or two substituents, eachindependently selected from the group consisting of halogen, C₁-C₆alkyl, haloalkyl, hydroxy, C₁-C₃ alkoxy, C₃-C₇ cycloalkyl, and 5- to10-membered monocyclic, bicyclic fused, or spiro heterocyclyl.28A. The compound of embodiment 27A, wherein R^(4a) is phenyl optionallysubstituted with fluoro or methoxy.29A. The compound of any one of embodiments 21A-24A, wherein R^(4a) is5- to 10-membered monocyclic or bicyclic fused heteroaryl optionallysubstituted with one or two substituents, each independently selectedfrom the group consisting of halogen, C₁-C₆ alkyl, haloalkyl, hydroxy,C₁-C₃ alkoxy, C₃-C₇ cycloalkyl, and 5- to 10-membered monocyclic,bicyclic fused, or spiro heterocyclyl.30A. The compound of embodiment 29A, wherein R^(4a) is pyridinyl orquinolinyl, optionally substituted with fluoro, methoxy, or methyl.31A. The compound of any one of embodiments 21A-24A, wherein R^(4a) isC₃-C₇ cycloalkyl, optionally substituted with one or two substituents,each independently selected from the group consisting of halogen, C₁-C₆alkyl, haloalkyl, hydroxy, C₁-C₃ alkoxy, C₃-C₇ cycloalkyl, and 5- to10-membered monocyclic, bicyclic fused, or spiro heterocyclyl.32A. The compound of embodiment 31A, wherein R^(4a) is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted withmethyl, trifluoromethyl, fluoro, or hydroxy.33A. The compound of any one of embodiments 21A-24A, wherein R^(4a) is a5- or 6-membered heterocyclyl, optionally substituted with one or twosubstituents, each independently selected from the group consisting ofhalogen, C₁-C₆ alkyl, haloalkyl, hydroxy, C₁-C₃ alkoxy, oxo, C₃-C₇cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiroheterocyclyl.34A. The compound of embodiment 33A, wherein R^(4a) is selected from thegroup consisting of tetrahydrofuranyl, pyrrolidinyl, andtetrahydropyranyl, optionally substituted with one or two substituents,each independently selected from the group consisting of methyl and oxo.35A. The compound of any one of embodiments 21A-24A, wherein R^(4a) is(C₆-C₁₀ aryl)-C₁-C₃ alkyl or (5- to 10-membered monocyclicheteroaryl)-C₁-C₃ alkyl, optionally substituted with one or twosubstituents, each independently selected from the group consisting ofhalogen, C₁-C₆ alkyl, haloalkyl, hydroxy, C₁-C₃ alkoxy, C₃-C₇cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiroheterocyclyl.36A. The compound of embodiment 35A, wherein R^(4a) is phenyl-methyl orpyridinyl-methyl.37A. The compound of any one of embodiments 21A-23A, wherein R^(4a) andR^(4b) taken together with the atom to which each is attached form a 5-to 7-membered heterocyclyl.38A. The compound of embodiment 37A, wherein R^(4a) and R^(4b) takentogether with the atom to which each is attached form a 6-memberedheterocyclyl selected from the group consisting of piperidinyl,morpholinyl, and piperazinyl.39A. The compound of any one of embodiments 21A or 25A-36A, whereinR^(4b) and R^(4c) taken together with the atom to which each is attachedform a 5- to 7-membered heterocyclyl optionally substituted one or twotimes with C₁-C₃ alkyl.40A. The compound of embodiment 39A, wherein R^(4b) and R^(4c) takentogether with the atom to which each is attached form a piperidin-2-oneor a pyrrolidine-2-one, optionally substituted one or two times withC₁-C₃ alkyl.41A. The compound of any one of embodiments 1A-17A, wherein R⁴ is

42A. The compound of embodiment 41A, wherein R^(4g) is phenyl or methyl.43A. The compound of any one of embodiments 1A-15A, wherein R³ and R⁴taken together with the nitrogen atom to which each is attached form a7-membered monocyclic heterocyclyl containing one or two heteroatoms.44A. The compound of embodiment 43A, wherein R³ and R⁴ taken togetherwith the nitrogen atom to which each is attached form a 7-memberedmonocyclic heterocyclyl containing one heteroatom, wherein saidheterocyclyl is optionally substituted once with methyl or oxo.45A. The compound of embodiment 43A, wherein R³ and R⁴ taken togetherwith the nitrogen atom to which each is attached form a 7-memberedmonocyclic heterocyclyl containing two heteroatoms, wherein saidheteroatoms are N or O, and said heterocyclyl is optionally substitutedonce with phenyl, methyl, or oxo, and wherein said phenyl is optionallysubstituted with methoxy.46A. The compound of any one of embodiments 1A-15A, wherein R³ and R⁴taken together with the nitrogen atom to which each is attached form an11-membered bicyclic fused heterocyclyl containing one heteroatom,optionally substituted with methoxy.47A. The compound of any one of embodiments 1A-46A, wherein p is 1.1B. A compound of Formula (I′):

or a pharmaceutically acceptable salt thereof; wherein,

Z is N or CH;

Ring B is

wherein

indicates the point of attachment to the remainder of the molecule;

-   -   R⁶, in each instance, is selected from the group consisting of        halogen, hydroxy, C₁-C₃ alkoxy, C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃        alkyl, hydroxy-C₁-C₆ alkoxy, hydroxy-C₁-C₃-alkyl, cyano,        —NR^(G)R^(H), halo-C₁-C₃ alkoxy, —O—(CH₂)_(u)—R^(bb), halo-C₁-C₃        alkyl, —O—R^(cc)—O—R^(dd), 5- to 7-membered monocyclic        heteroaryl, and C₃-C₆ cycloalkyl; wherein,        -   u is an integer from 0 to 6;        -   R^(bb) is 4- to 7-membered monocyclic heterocyclyl, C₃-C₇            cycloalkyl, or —NR^(G)R^(H);        -   R^(cc) and R^(dd) are each independently C₁-C₃ alkyl;            -   wherein, said cycloalkyl, heterocyclyl, or heteroaryl is                optionally substituted with one or two substituents,                each independently selected from the group consisting of                hydroxy, C₁-C₃ alkoxy, and C₁-C₃ alkyl;    -   and,        -   R^(G) and R^(H) are each independently hydrogen,            —C(O)R^(Ga), or C₁-C₃ alkyl; wherein,            -   R^(Ga) is C₁-C₃ alkyl or hydrogen;

or,

-   -   two R⁶ groups, taken together with the atom to which each is        attached, form a 5- or 6-membered monocyclic heterocyclyl fused        with Ring B, a C₄-C₇ cycloalkyl fused with Ring B, a phenyl        fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl        fused with Ring B; wherein,        -   said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused            with ring B is optionally substituted with one or two            substituents, each independently selected from the group            consisting of C₁-C₃ alkoxy, hydroxy, hydroxy-C₁-C₃-alkyl,            C₁-C₃ alkyl, C₃-C₇ cycloalkyl, and 5- or 6-membered            monocyclic heterocyclyl;    -   n is 0, 1, 2, or 3;    -   Y¹, Y², Y³, and Y⁴ are each independently selected from the        group consisting of CH, N, NH, O, S, SH, S—R⁶, N—R⁶, and C—R⁶,        provided that 1 or 2 of Y¹, Y², Y³, and Y⁴ can be N, N—R⁶, NH,        O, SH or S—R⁶;    -   f is 0 or 1;

p is 1 or 2;

R^(x), in each instance, is halogen, C₁-C₆ alkyl, C₁-C₃ alkoxy, hydroxy,or cyano;

m is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, C₁-C₃ alkyl,hydroxy-C₁-C₃ alkyl, cyclopropyl, and phenyl;

R⁴ is selected from the group consisting of:

-   -   i. (5- to 10-membered monocyclic or fused bicyclic        heteroaryl)-C₁-C₃ alkyl branched or linear, or (6- or 7-membered        monocyclic heterocyclyl)-C₁-C₃ alkyl branched or linear;        wherein,        -   said heteroaryl or heterocyclyl is optionally substituted            with one or two substituents, each independently selected            from the group consisting of C₆-C₁₀ monocyclic or fused            bicyclic aryl, C₃-C₇ cycloalkyl, 5- or 6-membered            heteroaryl, and 5- to 7-membered monocyclic heterocyclyl,            and wherein said aryl, cycloalkyl, heteroaryl, or            heterocyclyl is optionally substituted with one or two            substituents, each individually selected from the group            consisting of C₁-C₃ alkyl, halogen, and hydroxy; and,        -   when p is 1, C₁-C₃ alkyl in the (5- to 10-membered            monocyclic or fused bicyclic heteroaryl)-C₁-C₃ alkyl is            linear;

and,

-   -   ii.

-   -   wherein,        -   R^(4a) and R^(4g) are each independently selected from the            group consisting of hydrogen, C₁-C₆ alkyl, hydroxy-C₁-C₆            alkyl, C₁-C₃ alkoxy-C₁-C₆ alkyl, C₃-C₇ cycloalkyl, 5- to            10-membered monocyclic, fused bicyclic, bridged bicyclic, or            spiro heterocyclyl, C₆-C₁₀ monocyclic or fused bicyclic            aryl, 5- to 10-membered monocyclic or fused bicyclic            heteroaryl, (C₆-C₁₀ monocyclic or fused bicyclic aryl)-C₁-C₃            alkyl, and (5- to 10-membered monocyclic or fused bicyclic            heteroaryl)-C₁-C₃ alkyl;            -   wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl,                aryl-alkyl, or heteroaryl-alkyl of R^(4a) or R^(4g) is                optionally substituted with one, two, or three                substituents, each independently selected from the group                consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl,                hydroxy, C₁-C₃ alkoxy, halo-C₁-C₃ alkoxy, oxo, C₃-C₇                cycloalkyl, and 5- to 10-membered monocyclic, fused                bicyclic, or spiro heterocyclyl;        -   R^(4b) is hydrogen or C₁-C₆ alkyl; or        -   R^(4a) and R^(4b) taken together with the atom to which each            is attached form a 5- to 10-membered monocyclic, fused            bicyclic, or bridged bicyclic heterocyclyl, optionally            substituted with one or two substituents, each independently            selected from the group consisting of halogen, C₁-C₆ alkyl,            halo-C₁-C₃ alkyl, hydroxy, and C₁-C₃ alkoxy; or        -   R^(4b) and R^(4c) taken together with the atom to which each            is attached form a 5- to 7-membered monocyclic heterocyclyl            optionally substituted with one, two, or three substituents,            each independently selected from the group consisting of            hydroxy, halogen, and C₁-C₃ alkyl; or        -   R^(4c) and R^(4d) are each independently selected from the            group consisting of hydrogen, C₁-C₃ alkoxy, hydroxy, C₁-C₃            alkyl-thio-C₁-C₃ alkyl, hydroxy-C₁-C₆ alkyl, C₁-C₆            alkoxy-C₁-C₃ alkyl, C₃-C₇ cycloalkyl, and C₁-C₃ alkyl; or        -   R^(4c) and R^(4d) taken together with the atom to which each            is attached form a C₃-C₇ cycloalkyl;

or, when p is 1,

-   -   R³ and R⁴ taken together with the nitrogen atom to which each is        attached can form a:        -   i. 7-membered fused bicyclic heterocyclyl, 7-membered            bridged bicyclic heterocyclyl, or 7-membered monocyclic            heterocyclyl containing one or two heteroatoms;            -   wherein when said 7-membered monocyclic heterocyclyl                contains one heteroatom, said heterocyclyl is optionally                substituted with one, two, or three substituents, each                independently selected from the group consisting of oxo,                halogen, hydroxy, C₁-C₃ alkoxy, cyano, and C₁-C₃ alkyl;                and,            -   when said 7-membered monocyclic heterocyclyl contains                two heteroatoms, said heteroatoms are each independently                N or O, and said heterocyclyl is optionally substituted                with one, two, or three substituents, each independently                selected from the group consisting of C₁-C₃ alkyl,                cyano, oxo, halogen, halo-C₁-C₃ alkyl, and C₆-C₁₀                monocyclic or fused bicyclic aryl; and                -   wherein said aryl is optionally substituted with one                    or two substituents, each individually selected from                    the group consisting of C₁-C₃ alkoxy, hydroxy,                    halogen, and C₁-C₃ alkyl;        -   ii. 4- or 6-membered monocyclic heterocyclyl containing one            heteroatom;            -   wherein said 4-membered monocyclic heterocyclyl is                optionally substituted with one or two substituents,                each independently selected from the group consisting of                halogen, C₁-C₃ alkoxy, oxo, and                —(CH₂)_(s)C(═O)NR^(k)R^(l); wherein,                -   s is 0, 1, 2, or 3;                -   R^(k) is hydrogen or C₁-C₃ alkyl; and                -   R^(l) is selected from the group consisting of                    hydrogen, hydroxy, C₁-C₃ alkyl, C₃-C₇ cycloalkyl,                    and C₆-C₁₀ monocyclic or fused bicyclic aryl;                    wherein said 6-membered monocyclic heterocyclyl is                    optionally substituted with one or two substituents,                    each independently selected from the group                    consisting of C₁-C₃ alkoxy, oxo, halogen, cyano, and                    —NR^(q)R^(w); wherein,                -   R^(q) is hydrogen or C₁-C₃ alkyl; and                -   R^(w) is C₆-C₁₀ monocyclic or fused bicyclic aryl or                    C₃-C₇ cycloalkyl, wherein said aryl or cycloalkyl is                    optionally substituted with one or two substituents,                    each independently selected from the group                    consisting of halogen, C₁-C₃ alkyl, hydroxy, and                    C₁-C₃ alkoxy;    -   or,        -   iii. 8-, 9-, 10- or 11-membered fused bicyclic heterocyclyl,            or 12-membered bicyclic bridged and fused heterocyclyl,            wherein said 8-, 9-, or 11-membered heterocyclyl contains            one heteroatom and said 10- or 12-membered heterocyclyl            contains one or two heteroatoms; and wherein said 10-, 11-,            or 12-membered heterocyclyl is optionally substituted with            one, two, or three substituents, each independently selected            from the group consisting of halogen, C₁-C₃ alkyl, C₁-C₃            alkoxy, and hydroxy;

or, when p is 2,

-   -   R³ and R⁴ taken together with the nitrogen atom to which each is        attached can form a:        -   i. 6-membered monocyclic heterocyclyl containing one            heteroatom, optionally substituted with one or two            substituents, each independently selected from the group            consisting of halogen, hydroxy-(C₁-C₆ alkyl), hydroxy, oxo,            and C₁-C₃ alkoxy; or        -   ii. 4- or 7-membered monocyclic heterocyclyl containing one            or two heteroatoms, or 7-, 8-, 9-, 10-, or 11-membered            bridged bicyclic, fused bicyclic, or spiro heterocyclyl            containing one, two, or three heteroatoms, optionally            substituted with one or two substituents, each independently            selected from the group consisting of halogen, oxo, cyano,            C₁-C₃ alkyl, hydroxy, —NR^(G)R^(H), and            —(CH₂)_(s)C(═O)NR^(k)R^(l);

provided that when the structure of Formula (I) is

* is

and ** is

; or

* is

and ** is

;

and,

wherein the compound of Formula (I) is not:

-   N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine;-   4-(piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;-   4-(azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;-   1-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one;    or-   2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane;    or a salt thereof.    1C. A compound of Formula (I′):

or a pharmaceutically acceptable salt thereof; wherein,

Z is N or CH;

Ring B is

wherein

indicates the point of attachment to the remainder of the molecule;

-   -   R⁶, in each instance, is selected from the group consisting of        halogen, hydroxy, C₁-C₃ alkoxy, C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃        alkyl, hydroxy-C₁-C₁₀ alkoxy, hydroxy-C₁-C₁₀-alkyl, cyano,        —NR^(G)R^(H), halo-C₁-C₃ alkoxy, —O—(C₁-C₆ alkyl)-R^(bb),        —O—R^(bb), —(C₁-C₆ alkyl)-NR^(GI)R^(HI), —S—C₁-C₃ alkyl,        —S—C₁-C₃ alkyl-NR^(G1)R^(H1), halo-C₁-C₃ alkyl,        —O—R^(cc)—O—R^(dd), 5- to 7-membered monocyclic heteroaryl, and        C₃-C₆ cycloalkyl; wherein,    -   the alkyl moiety in hydroxy-C₁-C₁₀ alkoxy or —O—(C₁-C₆        alkyl)-R^(bb) is optionally substituted with cyano, hydroxy,        hydroxy-C₁-C₃-alkyl, halogen, or C₁-C₃ alkoxy;        -   R^(bb) is 4- to 7-membered monocyclic or bridged            heterocyclyl, C₃-C₇ cycloalkyl, 5- or 6-membered monocyclic            heteroaryl, —SO₂—C₁-C₃ alkyl, —S—C₁-C₃ alkyl,            —C(O)NR^(G1)R^(H1), or —NR^(G)R^(H);        -   R^(cc) is C₁-C₃ alkyl; and        -   R^(dd) is C₁-C₃ alkyl or a 6-membered heteroaryl;            -   wherein, said cycloalkyl, heterocyclyl, or heteroaryl of                R⁶, R^(bb), or R^(dd) is optionally substituted with one                or two substituents, each independently selected from                the group consisting of hydroxy, halogen, halo-C₁-C₃                alkyl, oxo, C₁-C₃ alkoxy, and C₁-C₃ alkyl;        -   R^(G1) and R^(H1) are each independently hydrogen or C₁-C₃            alkyl;    -   and,        -   R^(G) and R^(H) are each independently hydrogen,            —C(O)R^(Ga), or optionally deuterated C₁-C₃ alkyl; wherein,            -   R^(Ga) is C₁-C₃ alkyl or hydrogen;

or,

-   -   two R⁶ groups, taken together with the atom to which each is        attached, form a 5- or 6-membered monocyclic heterocyclyl fused        with Ring B, a C₄-C₇ cycloalkyl fused with Ring B, a phenyl        fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl        fused with Ring B; wherein,        -   said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused            with ring B is optionally substituted with one or two            substituents, each independently selected from the group            consisting of C₁-C₃ alkoxy, hydroxy, hydroxy-C₁-C₃-alkyl,            C₁-C₃ alkyl, C₃-C₇ cycloalkyl, and 5- or 6-membered            monocyclic heterocyclyl;    -   n is 0, 1, 2, or 3;    -   Y¹, Y², Y³, and Y⁴ are each independently selected from the        group consisting of CH, N, NH, O, S, SH, S—R⁶, N—R⁶, and C—R⁶,        provided that 1 or 2 of Y¹, Y², Y³, and Y⁴ can be N, N—R⁶, NH,        O, SH or S—R⁶;    -   f is 0 or 1;

p is 1 or 2;

R^(x), in each instance, is halogen, C₁-C₆ alkyl, C₁-C₃ alkoxy, hydroxy,oxo, or cyano;

m is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, optionallydeuterated C₁-C₃ alkyl, hydroxy-C₁-C₃ alkyl, halo-C₁-C₃ alkyl,cyclopropyl, and phenyl;

R⁴ is selected from the group consisting of:

-   -   i. (5- to 10-membered monocyclic or fused bicyclic        heteroaryl)-C₁-C₃ alkyl, or (6- or 7-membered monocyclic        heterocyclyl)-C₁-C₃ alkyl; wherein,        -   said heteroaryl or heterocyclyl is optionally substituted            with one or two substituents, each independently selected            from the group consisting of C₆-C₁₀ monocyclic or fused            bicyclic aryl, C₃-C₇ cycloalkyl, 5- or 6-membered            heteroaryl, —(C₁-C₃ alkyl)-T, and 5- to 7-membered            monocyclic heterocyclyl;            -   T is selected from the group consisting of C₆-C₁₀                monocyclic or fused bicyclic aryl, C₃-C₇ cycloalkyl, 5-                or 6-membered heteroaryl, and 5- to 7-membered                monocyclic heterocyclyl; and,                -   wherein T or said aryl, cycloalkyl, heteroaryl, or                    heterocyclyl substituent of R⁴ is optionally                    substituted with one or two substituents, each                    individually selected from the group consisting of                    C₁-C₃ alkyl, halogen, and hydroxy; and        -   when p is 1, C₁-C₃ alkyl in the (5- to 10-membered            monocyclic or fused bicyclic heteroaryl)-C₁-C₃ alkyl is            linear;

and,

-   -   ii.

-   -   wherein,        -   R^(4a) and R^(4g) are each independently selected from the            group consisting of hydrogen, C₁-C₁₀ alkyl, hydroxy-C₁-C₆            alkyl, halo-C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₆ alkyl, —C₁-C₆            alkyl-NR^(J1)R^(J2), C₃-C₇ cycloalkyl, 4- to 10-membered            monocyclic, fused bicyclic, bridged bicyclic, or spiro            heterocyclyl, C₆-C₁₀ monocyclic or fused bicyclic aryl, 5-            to 10-membered monocyclic or fused bicyclic heteroaryl,            (C₆-C₁₀ monocyclic or fused bicyclic aryl)-C₁-C₃ alkyl, and            (5- to 10-membered monocyclic or fused bicyclic            heteroaryl)-C₁-C₃ alkyl;            -   R^(J1) and R^(J2) are independently hydrogen or C₁-C₃                alkyl;            -   wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl,                aryl-alkyl, or heteroaryl-alkyl of R^(4a) or R^(4g) is                optionally substituted with one, two, or three                substituents, each independently selected from the group                consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl,                hydroxy, C₁-C₃ alkoxy, halo-C₁-C₃ alkoxy, oxo, C₃-C₇                cycloalkyl, and 5- to 10-membered monocyclic, fused                bicyclic, or spiro heterocyclyl;        -   R^(4b) is hydrogen or C₁-C₆ alkyl; or        -   R^(4a) and R^(4b) taken together with the atom to which each            is attached form a 5- to 10-membered monocyclic, fused            bicyclic, or bridged bicyclic heterocyclyl, optionally            substituted with one or two substituents, each independently            selected from the group consisting of halogen, C₁-C₆ alkyl,            halo-C₁-C₃ alkyl, hydroxy, and C₁-C₃ alkoxy; or            -   R^(4b) and R^(4c) taken together with the atom to which                each is attached form a 5- to 7-membered monocyclic                heterocyclyl optionally substituted with one, two, or                three substituents, each independently selected from the                group consisting of hydroxy, halogen, and C₁-C₃ alkyl;                or        -   R^(4c) and R^(4d) are each independently selected from the            group consisting of hydrogen, C₁-C₃ alkoxy, hydroxy, C₁-C₃            alkyl-thio-C₁-C₃ alkyl, hydroxy-C₁-C₆ alkyl, C₁-C₆            alkoxy-C₁-C₃ alkyl, C₃-C₇ cycloalkyl, and C₁-C₃ alkyl; or        -   R^(4c) and R^(4d) taken together with the atom to which each            is attached form a C₃-C₇ cycloalkyl;

or, when p is 1,

-   -   R³ and R⁴ taken together with the nitrogen atom to which each is        attached can form a:        -   i. 7-membered fused bicyclic heterocyclyl, 7-membered            bridged bicyclic heterocyclyl, or 7-membered monocyclic            heterocyclyl containing one or two heteroatoms;            -   wherein when said 7-membered monocyclic heterocyclyl                contains one heteroatom, said heterocyclyl is optionally                substituted with one, two, or three substituents, each                independently selected from the group consisting of oxo,                halogen, hydroxy, C₁-C₃ alkoxy, cyano, and C₁-C₃ alkyl;                and,            -   when said 7-membered monocyclic heterocyclyl contains                two heteroatoms, said heteroatoms are each independently                N or O, and said heterocyclyl is optionally substituted                with one, two, or three substituents, each independently                selected from the group consisting of C₁-C₃ alkyl,                cyano, oxo, halogen, halo-C₁-C₃ alkyl, and C₆-C₁₀                monocyclic or fused bicyclic aryl; and                -   wherein said aryl is optionally substituted with one                    or two substituents, each individually selected from                    the group consisting of C₁-C₃ alkoxy, hydroxy,                    halogen, and C₁-C₃ alkyl;        -   ii. 4- or 6-membered monocyclic heterocyclyl containing one            heteroatom;            -   wherein said 4-membered monocyclic heterocyclyl is                optionally substituted with one or two substituents,                each independently selected from the group consisting of                halogen, C₁-C₃ alkoxy, oxo, and                —(CH₂)_(s)C(═O)NR^(k)R^(l); wherein,                -   s is 0, 1, 2, or 3;                -   R^(k) is hydrogen or C₁-C₃ alkyl; and                -   R^(l) is selected from the group consisting of                    hydrogen, hydroxy, C₁-C₃ alkyl, C₃-C₇ cycloalkyl,                    and C₆-C₁₀ monocyclic or fused bicyclic aryl;            -   wherein said 6-membered monocyclic heterocyclyl is                optionally substituted with one or two substituents,                each independently selected from the group consisting of                C₁-C₃ alkoxy, oxo, halogen, cyano, and —NR^(q)R^(w);                wherein,                -   R^(q) is hydrogen or C₁-C₃ alkyl; and                -   R^(w) is C₆-C₁₀ monocyclic or fused bicyclic aryl or                    C₃-C₇ cycloalkyl, wherein said aryl or cycloalkyl is                    optionally substituted with one or two substituents,                    each independently selected from the group                    consisting of halogen, C₁-C₃ alkyl, hydroxy, and                    C₁-C₃ alkoxy;    -   or,        -   iii. 8-, 9-, 10- or 11-membered fused bicyclic heterocyclyl,            or 12-membered bicyclic bridged and fused heterocyclyl,            wherein said 8-, 9-, or 11-membered heterocyclyl contains            one heteroatom and said 10- or 12-membered heterocyclyl            contains one or two heteroatoms; and wherein said 10-, 11-,            or 12-membered heterocyclyl is optionally substituted with            one, two, or three substituents, each independently selected            from the group consisting of halogen, C₁-C₃ alkyl, C₁-C₃            alkoxy, and hydroxy;

or, when p is 2,

-   -   R³ and R⁴ taken together with the nitrogen atom to which each is        attached can form a:        -   i. 6-membered monocyclic heterocyclyl containing one            heteroatom, optionally substituted with one or two            substituents, each independently selected from the group            consisting of halogen, hydroxy-(C₁-C₆ alkyl), hydroxy, oxo,            and C₁-C₃ alkoxy; or        -   ii. 4- or 7-membered monocyclic heterocyclyl containing one            or two heteroatoms, or 7-, 8-, 9-, 10-, or 11-membered            bridged bicyclic, fused bicyclic, or spiro heterocyclyl            containing one, two, or three heteroatoms, optionally            substituted with one or two substituents, each independently            selected from the group consisting of halogen, oxo,    -   cyano, C₁-C₃ alkyl, hydroxy, —NR^(G)R^(H), and        —(CH₂)_(s)C(═O)NR^(k)R^(l);

provided that when the structure of Formula (I) is

* is

and ** is

; or

* is

and ** is

;

and,

wherein the compound of Formula (I) is not:

-   N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine;-   4-(piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;-   4-(azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;-   1-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one;    or-   2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane;    or a salt thereof.    2B. The compound of embodiment 1B or 1C, or a pharmaceutically    acceptable salt thereof, wherein p is 1.    3B. The compound of embodiment 1B, 2B, or 1C, or a pharmaceutically    acceptable salt thereof, wherein Z is N.    4B. The compound of any one of embodiments 1B-3B or 1C, or a    pharmaceutically acceptable salt thereof, wherein Y¹, Y², Y³, and Y⁴    are each CH or C—R⁶.    5C. The compound of embodiment 4B or 1C, or a pharmaceutically    acceptable salt thereof, wherein Y¹ is CH, Y² is C—R⁶, Y³ is CH, and    Y⁴ is CH.    5B. The compound of any one of embodiments 1B-3B or 1C, or a    pharmaceutically acceptable salt thereof, wherein Y³ is N and Y¹,    Y², and Y⁴ are each CH or C—R⁶.    6B. The compound of any one of embodiments 1B-3B or 1C, or a    pharmaceutically acceptable salt thereof, wherein Y² is N and Y¹,    Y³, Y⁴ are each CH or C—R⁶.    7B. The compound of any one of embodiments 1B-3B or 1C, or a    pharmaceutically acceptable salt thereof, wherein Y¹ is N and Y²,    Y³, and Y⁴ are each CH or C—R⁶.    8B. The compound of any one of embodiments 1B-7B, or a    pharmaceutically acceptable salt thereof, wherein R⁶, in each    instance, is selected from the group consisting of halogen, hydroxy,    C₁-C₃ alkoxy, C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃ alkyl, hydroxy-C₁-C₆    alkoxy, hydroxy-C₁-C₃ alkyl, —O—(CH₂)_(u)—R^(bb), halo-C₁-C₃ alkoxy,    —O—R^(cc)—O—R^(dd), halo-C₁-C₃ alkyl, and —NR^(G)R^(H); wherein,

R^(bb) is —NR^(G)R^(H);

u is an integer from 1 to 3;

R^(G) and R^(H) are each independently hydrogen or C₁-C₃ alkyl; and

R^(cc) and R^(dd) are each independently C₁-C₃ alkyl.

9C. The compound of any one of embodiments 1C, 2B-8B or 5C, or apharmaceutically acceptable salt thereof, wherein R⁶, in each instance,is selected from the group consisting of halogen, hydroxy, C₁-C₃ alkoxy,C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃ alkyl, hydroxy-C₁-C₁₀ alkoxy,hydroxy-C₁-C₁₀-alkyl, —O—(C₁-C₆ alkyl)-R^(bb), halo-C₁-C₃ alkoxy,—O—R^(cc)—O—R^(dd), halo-C₁-C₃ alkyl, —(C₁-C₆ alkyl)- NR^(GI)R^(HI),—S—CH₃, —S(CH₂)₂N(CH₃)₂, and —NR^(G)R^(H); wherein,

R^(bb) is —NR^(G)R^(H), —C(O)N(CH₃)₂, —S(O)₂CH₃, or —SCH₃;

R^(G) and R^(H) are each independently hydrogen, optionally deuteratedC₁-C₃ alkyl, or —C(O)R^(Ga), wherein R^(Ga) is C₁-C₃ alkyl;

R^(GI) and R^(HI) are each independently hydrogen or C₁-C₃ alkyl;

R^(cc) and R^(dd) are each independently C₁-C₃ alkyl; and,

wherein the alkyl moiety in hydroxy-C₁-C₁₀ alkoxy is optionallysubstituted with hydroxy, halogen, or C₁-C₃ alkoxy.

9B. The compound of any one of embodiments 1B-8B, 5C, or 9C, or apharmaceutically acceptable salt thereof, wherein R⁶, in each instance,is selected from the group consisting of methoxy, ethoxy, methyl,fluoro, chloro, ethyl, —N(CH₃)₂, hydroxy, —OCH₂CH₂OH, —CH₂OH, —CH₂OCH₃,—OCH₂CH₂NH₂, —OCH₂CH₂N(CH₃)₂, —OCH₂C(CH₃)₂OH, —OCH₂CF₃, —OCHF₂, —OCF₃,—OCH₂CH₂OCH₃, —OCH₂CH₂F, —OC(CH₃)₂CH₂OH, and —CH₂CH₂OH.10C. The compound of embodiment 9C, or a pharmaceutically acceptablesalt thereof, wherein R⁶, in each instance, is selected from the groupconsisting of methoxy, ethoxy, methyl, fluoro, chloro, ethyl, —N(CH₃)₂,hydroxy, —OCH₂CH₂OH, —CH₂OH, —CH₂OCH₃, —OCH₂CH₂NH₂, —OCH₂CH₂N(CH₃)₂,—OCH₂C(CH₃)₂OH, —OCH₂CF₃, —OCHF₂, —OCF₃, —OCH₂CH₂OCH₃, —OCH₂CH₂F,—OC(CH₃)₂CH₂OH, —OCH₂CH(CH₃)OH, —OCH₂CH₂NHC(O)CH₃, —OC(CH₃)₂CH₂N(CH₃)₂,—OCH(CH₃)CH₂OH, —OCH₂CH(CH(CH₃)₂)OH, —OCH₂CH(CH₂CH₃)OH,—OCH₂C(CH₂CH₃)₂OH, —OCH₂CH₂N(CH₂CH₃)₂, —OCH(CH₃)CH₂N(CH₃)₂,—OCH₂C(O)N(CH₃)₂, —OCH₂C(CH₃)₂N(C H₃)₂, —OCH₂CH(CH₂OH)OH,—OCH₂CH₂NH(CH₃), —OCH₂CH(CF₃)OH, —OCH₂C(CH₃)(CH₂CH₃)OH,—OCH₂CH(CH₂OCH₃)OH, —OCH₂CH(CH₂F)OH, —(CH₂)₃N(CH₃)₂, —(CH₂)₃N(CH₃)H,—O(CH₂)₂S(O)₂CH₃, —O(CH₂)₂SCH₃, —(CH₂)₂C(CH₃)₂OH, —OCH₂CH₂N(CD₃)₂, and—CH₂CH₂OH.10B. The compound of embodiment 9B, 9C, or 10C, or a pharmaceuticallyacceptable salt thereof, wherein R⁶, in each instance, is methoxy,—OCH₂CH₂OH, or —OCH₂C(CH₃)₂OH.11C. The compound of embodiment 10C, or a pharmaceutically acceptablesalt thereof, wherein R⁶, in each instance, is methoxy, —OCH₂CH₂N(CH₃)₂,—OCH₂CH₂OH, or —OCH₂C(CH₃)₂OH.12C. The compound of embodiment 11C, or a pharmaceutically acceptablesalt thereof, wherein R⁶, in each instance, is —OCH₂CH₂N(CH₃)₂ or—OCH₂C(CH₃)₂OH.11B. The compound of any one of embodiments 1B-7B, or a pharmaceuticallyacceptable salt thereof, wherein R⁶, in each instance, is selected fromthe group consisting of —O—(CH₂)_(u)—R^(bb), and C₃-C₆ cycloalkyl;wherein,

u is an integer from 0 to 3;

R^(bb) is 4- to 7-membered monocyclic heterocyclyl or C₃-C₇ cycloalkyl;and

-   -   wherein said cycloalkyl or heterocyclyl is optionally        substituted with one or two substituents, each independently        selected from the group consisting of hydroxy, C₁-C₃ alkoxy, and        C₁-C₃ alkyl.        12B. The compound of embodiment 11B, or a pharmaceutically        acceptable salt thereof, wherein R⁶, in each instance, is        selected from the group consisting of cyclopropyl and        —O—(CH₂)_(u)—R^(bb); wherein,

u is 0, 1, or 2; and

R^(bb) is selected from the group consisting of cyclopropyl, cyclobutyl,tetrahydrofuranyl, oxetanyl, and pyrrolidinyl, each optionallysubstituted with hydroxy or methyl.

13C. The compound of any one of embodiments 1C, 2B-8B or 5C, or apharmaceutically acceptable salt thereof, wherein R⁶, in each instance,is selected from the group consisting of —O—(C₁-C₆ alkyl)-R^(bb),—O—R^(bb), —O—R^(cc)—O—R^(dd), 5- to 7-membered monocyclic heteroaryl,and C₃-C₆ cycloalkyl; wherein,

R^(cc) is C₁-C₃ alkyl and R^(dd) is 6-membered heteroaryl;

R^(bb) is 4- to 7-membered monocyclic or bridged heterocyclyl, 5- or6-membered monocyclic heteroaryl, or C₃-C₇ cycloalkyl; and

-   -   wherein said cycloalkyl, heteroaryl, or heterocyclyl of R⁶,        R^(bb), or R^(dd) is optionally substituted with one or two        substituents, each independently selected from the group        consisting of hydroxy, halogen, C₁-C₃ alkoxy, oxo, halo-C₁-C₃        alkyl, and C₁-C₃ alkyl.        14C. The compound of embodiment 13C, or a pharmaceutically        acceptable salt thereof, wherein R⁶, in each instance, is        selected from the group consisting of cyclopropyl, —O—R^(bb),        —O—(CH₂)—R^(bb), and —O—(CH₂)₂—R^(bb), —O—(CH₂)₂—O-pyridazinyl,        optionally C₁-C₃ alkyl-substituted imidazolyl; wherein,

R^(bb) is selected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranol, oxetanyl,dioxolanyl, azetidinyl, morpholinyl, piperazinyl,2-oxa-5-azabicyclo[2.2.1]heptane, imidazolyl, tetrazolyl, pyridazinyl,piperidinyl, thiomorpholinyl, and pyrrolidinyl, each optionallysubstituted with hydroxy, oxo,

fluoro, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, methoxy, ethyl, or methyl.

15C. The compound of embodiment 14C, or a pharmaceutically acceptablesalt thereof, wherein R⁶, in each instance, is selected from the groupconsisting of

where

indicates the point of attachment to Ring B.13B. The compound of embodiment 12B, 14C, or 15C, or a pharmaceuticallyacceptable salt thereof, wherein R⁶, in each instance, is selected fromthe group consisting of

where

indicates the point of attachment to Ring B.16C. The compound of embodiment 15C, or a pharmaceutically acceptablesalt thereof, wherein R⁶ is

14B. The compound of embodiment 13B or 13-16C, or a pharmaceuticallyacceptable salt thereof, wherein R⁶ is

15B. The compound of any one of embodiments 1B-7B or 1C, or apharmaceutically acceptable salt thereof, wherein two R⁶ groups, takentogether with the atom to which each is attached, form a 5- or6-membered monocyclic heterocyclyl fused with Ring B, a C₄-C₇ cycloalkylfused with Ring B, a phenyl fused with Ring B, or a 5- or 6-memberedmonocyclic heteroaryl fused with Ring B, each optionally substitutedwith one or two substituents, each independently selected from the groupconsisting of C₁-C₃ alkoxy, hydroxy, hydroxy-C₁-C₃-alkyl, C₁-C₃ alkyl,C₃-C₇ cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl.16B. The compound of any one of embodiments 1B-7B or 1C, or apharmaceutically acceptable salt thereof, wherein two R⁶ groups, takentogether with the atom to which each is attached, form a pyrazolyl,dioxanyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, dioxolanyl, orphenyl ring fused with Ring B, wherein said ring is optionallysubstituted with one substituent selected from the group consisting ofhydroxy, methoxy, tetrahydropyranyl, —CH₂OH, and methyl.17B. The compound of embodiment 16B, or a pharmaceutically acceptablesalt thereof, wherein two R⁶ groups, taken together with the atom towhich each is attached, form a ring selected from the group consistingof

fused with ring B, wherein the pair of

represent the attachment of the ring with Ring B.18B. The compound of embodiment 17B, or a pharmaceutically acceptablesalt thereof, wherein two R⁶ groups, taken together with the atom towhich each is attached, form a form a ring selected from the groupconsisting of

fused with Ring B.18.bb The compound of any one of embodiments 15B-18B, wherein Ring B isselected from the group consisting of

19B. The compound of any one of embodiments 1B-19B, 1C, 5C, 9C, 1° C.,11C, 12C, 13C, 14C, 15C, or 16C, or a pharmaceutically acceptable saltthereof, wherein f is 1.20B. The compound of embodiment 1B, 2B, 3B, or 1C, or a pharmaceuticallyacceptable salt thereof, wherein f is 0, and Ring B is

21B. The compound of embodiment 20B, or a pharmaceutically acceptablesalt thereof, wherein Ring B is

wherein,

n is 0 or 1; and

Y² and Y³ are each independently selected from the group consisting ofCH, N, NH, NR⁶, S, O, and CR⁶, provided that only one of Y² and Y³ canbe N, NH, NR⁶, S, or O.

22B. The compound of embodiment 20B or 21B, or a pharmaceuticallyacceptable salt thereof, wherein Ring B is selected from the groupconsisting of

23B. The compound of any one of embodiments 20B-22B, or apharmaceutically acceptable salt thereof, wherein R⁶, in each instance,is selected from the group consisting of C₁-C₃ alkyl and hydroxy-C₁-C₃alkyl.24B. The compound of embodiment 23B, or a pharmaceutically acceptablesalt thereof, wherein R⁶, in each instance, is selected from the groupconsisting of methyl, ethyl, n-propyl, —CH₂CH₂OH, and —CH₂CH₂CH₂OH.25B. The compound of any one of embodiments 1B-24B, 1C, 5C, 9C, 10C,11C, 12C, 13C, 14C, 15C, or 16C, or a pharmaceutically acceptable saltthereof, wherein n is 1.26B. The compound of any one of embodiments 1B-24B1C, 5C, 9C, 10C, 11C,12C, 13C, 14C, 15C, or 16C, or a pharmaceutically acceptable saltthereof, wherein n is 0.27B. The compound of any one of embodiments 1B-14B, 1C, 5C, 9C, 10C,11C, 12C, 13C, 14C, 15C, or 16C, or a pharmaceutically acceptable saltthereof, wherein n is 2.28B. The compound of embodiment 27B, wherein one R⁶ is selected from thegroup consisting of methyl and methoxy and the other R⁶ is selected fromthe group consisting of methyl, methoxy, halogen, and —OCH₂CH₂OH.31C. The compound of any one of embodiments 1-28B or 1C, 5C, 9C, 10C,11C, 12C, 13C, 14C, 15C, or 16C, or a pharmaceutically acceptable saltthereof, wherein R³ is selected from the group consisting of hydrogen,methyl, ethyl, phenyl, —CD₃, —CH₂CF₃, and —CH₂CH₂OH.29B. The compound of any one of embodiments 1B-28B1C, 5C, 9C, 10C, 11C,12C, 13C, 14C, 15C, 16C, or 31C, or a pharmaceutically acceptable saltthereof, wherein R³ is selected from the group consisting of hydrogen,methyl, ethyl, phenyl, and —CH₂CH₂OH.30B. The compound of embodiment 29B or 31C, or a pharmaceuticallyacceptable salt thereof, wherein R³ is methyl.33C. The compound of any one of embodiments 1B-30B or 1C, 5C, 9C, 10C,11C, 12C, 13C, 14C, 15C, 16C, or 31C, or a pharmaceutically acceptablesalt thereof, wherein R⁴ is a (5- to 10-membered monocyclic or fusedbicyclic heteroaryl)-methyl, wherein said heteroaryl is optionallysubstituted with one or two substituents, each independently selectedfrom the group consisting of phenyl, C₃-C₇ cycloalkyl, —(C₁-C₃alkyl)-phenyl, and 5- to 7-membered monocyclic heterocyclyl, and whereinsaid phenyl either alone or in —(C₁-C₃ alkyl)-phenyl, cycloalkyl, orheterocyclyl is optionally substituted with one or two substituents,each individually selected from the group consisting of C₁-C₃ alkyl,halogen, and hydroxy.31B. The compound of any one of embodiments 1B-30B or 33C, or apharmaceutically acceptable salt thereof, wherein R⁴ is a (5- to10-membered monocyclic or fused bicyclic heteroaryl)-methyl, whereinsaid heteroaryl is optionally substituted with one or two substituents,each independently selected from the group consisting of phenyl, C₃-C₇cycloalkyl, and 5- to 7-membered monocyclic heterocyclyl, and whereinsaid phenyl, cycloalkyl, or heterocyclyl is optionally substituted withone or two substituents, each individually selected from the groupconsisting of C₁-C₃ alkyl, halogen, and hydroxy.32B. The compound of embodiment 31B or 33C, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is a (6-membered heteroaryl)-methyl,wherein at least one of the ring atoms ortho to the attachment point insaid 6-membered heteroaryl is a nitrogen.35C. The compound of embodiment 33C or 32B, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is selected from the groupconsisting of pyridinyl-methyl, pyrimidinyl-methyl, benzoxazole-methyl,oxazolyl-methyl, and triazolyl-methyl, each optionally substituted withphenyl or benzyl, and wherein said phenyl is optionally substituted withone substituent selected from the group consisting of fluoro, methyl,and chloro.33B. The compound of embodiment 31B, 32B or 35C, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is selected from the groupconsisting of pyridinyl-methyl, pyrimidinyl-methyl, benzoxazole-methyl,and triazolyl-methyl, each optionally substituted with phenyl, andwherein said phenyl is optionally substituted with one substituentselected from the group consisting of fluoro, methyl, and chloro.36C. The compound of embodiment 35C, or a pharmaceutically acceptablesalt thereof, wherein R⁴ is selected from the group consisting of

34B. The compound of embodiment 33B or 36C, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is selected from the groupconsisting of

35B. The compound of any one of embodiments 1B-30B or 1C, 5C, 9C, 1° C.,11C, 12C, 13C, 14C, 15C, 16C, 31C, 33C, 35C, or 36C, or apharmaceutically acceptable salt thereof, wherein, wherein R⁴ is

36B. The compound of embodiment 35B, or a pharmaceutically acceptablesalt thereof, wherein R^(4c) is selected from the group consisting ofhydrogen, methyl, isopropyl, —CH₂OH, —CH₂OC(CH₃)₃, and —CH₂CH₂SCH₃; andR^(4d) is selected from the group consisting of hydrogen and methyl; or,R^(4c) and R^(4d) taken together with the atom to which each is attachedform a cyclopropyl ring.37B. The compound of embodiment 36B, or a pharmaceutically acceptablesalt thereof, wherein R^(4c) and R^(4d) are each hydrogen.37bb. The compound of embodiment 36B, or a pharmaceutically acceptablesalt thereof, wherein R^(4c) is hydrogen or methyl; and R^(4d) ishydrogen.37bbb. The compound of embodiment 36B or 37bb, or a pharmaceuticallyacceptable salt thereof, wherein R^(4c) is methyl; and R^(4d) ishydrogen.38B. The compound of any one of embodiments 35B-37B, or apharmaceutically acceptable salt thereof, wherein R^(4b) is hydrogen.39B. The compound of any one of embodiments 35B-38B, or apharmaceutically acceptable salt thereof, wherein R^(4a) is C₁-C₆ alkyl.42C. The compound of embodiment 39B, or a pharmaceutically acceptablesalt thereof, wherein R^(4a) is methyl, ethyl, isopropyl, tert-butyl, or3-methylpentan-3-yl.43C. The compound of embodiment 39B or 42C, or a pharmaceuticallyacceptable salt thereof, wherein R^(4a) is tert-butyl or isopropyl.40B. The compound of embodiment 39B or 42C, or a pharmaceuticallyacceptable salt thereof, wherein R^(4a) is tert-butyl.41B. The compound of any one of embodiments 35B-38B, or apharmaceutically acceptable salt thereof, wherein R^(4a) is phenyl,optionally substituted with one or two substituents, each independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃alkyl, hydroxy, C₁-C₃ alkoxy, C₃-C₇ cycloalkyl, and 5- to 10-memberedmonocyclic or fused bicyclic heterocyclyl.42B. The compound of embodiment 41B, or a pharmaceutically acceptablesalt thereof, wherein R^(4a) is phenyl optionally substituted with onesubstituent selected from the group consisting of fluoro, chloro,methyl, and methoxy.43B. The compound of embodiment 42B, wherein R^(4a) is selected from thegroup consisting of

44B. The compound of any one of embodiments 35B-38B, or apharmaceutically acceptable salt thereof, wherein R^(4a) is 5- to10-membered monocyclic or fused bicyclic heteroaryl optionallysubstituted with one or two substituents, each independently selectedfrom the group consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl,hydroxy, C₁-C₃ alkoxy, C₃-C₇ cycloalkyl, and 5- to 10-memberedmonocyclic, fused bicyclic, or spiro heterocyclyl.45B. The compound of embodiment 44B, or a pharmaceutically acceptablesalt thereof, wherein R^(4a) is pyridinyl, pyrimidinyl, pyrazolyl,isothiazolyl, pyridizinyl, or quinolinyl, optionally substituted withone substituent selected from the group consisting of fluoro, chloro,methoxy, azepanyl, cyclopropyl, —CF₃, —OCF₃, or methyl.46B. The compound of embodiment 45B, or a pharmaceutically acceptablesalt thereof, wherein R^(4a) is selected from the group consisting of

47B. The compound of any one of embodiments 35B-38B, or apharmaceutically acceptable salt thereof, wherein R^(4a) is C₃-C₇cycloalkyl, optionally substituted with one or two substituents, eachindependently selected from the group consisting of halogen, C₁-C₆alkyl, halo-C₁-C₃ alkyl, hydroxy, C₁-C₃ alkoxy, C₃-C₇ cycloalkyl, and 5-to 10-membered monocyclic or fused bicyclic heterocyclyl.48B. The compound of embodiment 47B, or a pharmaceutically acceptablesalt thereof, wherein R^(4a) is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andbicyclo[1.1.1]pentan-1-yl, optionally substituted with one or twosubstituents, each independently selected from the group consisting ofmethyl, —CF₃, fluoro, or hydroxy.52C. The compound of embodiment 48B, wherein R^(4a) is selected from thegroup consisting of

49B. The compound of embodiment 48B or 52C, wherein R^(4a) is selectedfrom the group consisting of

53C. The compound of any one of embodiments 35B-38B, or apharmaceutically acceptable salt thereof, wherein R^(4a) is a 4- to10-membered monocyclic or fused bicyclic heterocyclyl, optionallysubstituted with one or two substituents, each independently selectedfrom the group consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl,hydroxy, C₁-C₃ alkoxy, oxo, C₃-C₇ cycloalkyl, and 5- to 10-memberedmonocyclic or fused bicyclic heterocyclyl.50B. The compound of any one of embodiments 35B-38B or 53C, or apharmaceutically acceptable salt thereof, wherein R^(4a) is a 5- to10-membered monocyclic or fused bicyclic heterocyclyl, optionallysubstituted with one or two substituents, each independently selectedfrom the group consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl,hydroxy, C₁-C₃ alkoxy, oxo, C₃-C₇ cycloalkyl, and 5- to 10-memberedmonocyclic or fused bicyclic heterocyclyl.54C. The compound of embodiment 53C, or a pharmaceutically acceptablesalt thereof, wherein R^(4a) is selected from the group consisting oftetrahydrofuranyl, pyrrolidinyl, benzo[d][1,3]dioxolyl, oxetanyl, andtetrahydropyranyl, optionally substituted with one or two substituents,each independently selected from the group consisting of methyl,methoxy, and oxo.51B. The compound of embodiment 50B, or a pharmaceutically acceptablesalt thereof, wherein R^(4a) is selected from the group consisting oftetrahydrofuranyl, pyrrolidinyl, benzo[d][1,3]dioxolyl, andtetrahydropyranyl, optionally substituted with one or two substituents,each independently selected from the group consisting of methyl,methoxy, and oxo.55C. The compound of embodiment 54C, wherein R^(4a) is selected from thegroup consisting of

52B. The compound of embodiment 51B or 55C, wherein R^(4a) is selectedfrom the group consisting of

53B. The compound of any one of embodiments 35B-38B, or apharmaceutically acceptable salt thereof, wherein R^(4a) is (C₆-C₁₀monocyclic or fused bicyclic aryl)-C₁-C₃ alkyl or (5- to 10-memberedmonocyclic or fused bicyclic heteroaryl)-C₁-C₃ alkyl, optionallysubstituted with one or two substituents, each independently selectedfrom the group consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl,hydroxy, C₁-C₃ alkoxy, C₃-C₇ cycloalkyl, and 5- to 10-memberedmonocyclic, fused bicyclic heterocyclyl.54B. The compound of embodiment 53B, or a pharmaceutically acceptablesalt thereof, wherein R^(4a) is selected from the group consisting ofphenyl-methyl, 1-cyclobutyl-2-ethyl-5-methyl-1H-imidazolyl, andpyridinyl-methyl.57C. The compound of claim 53B, or a pharmaceutically acceptable saltthereof, wherein R^(4a) is selected from the group consisting of benzyl,2-(1-cyclobutyl-5-methyl-1H-imidazol-2-yl)ethyl, and pyridinyl-methyl.55B. The compound of embodiment 54B or 57C, or a pharmaceuticallyacceptable salt thereof, wherein R^(4a) is selected from the groupconsisting of

59C. The compound of any one of embodiments 35B-38B, or apharmaceutically acceptable salt thereof, wherein R^(4a) is selectedfrom the group consisting of hydroxy-C₁-C₆ alkyl, halo-C₁-C₃ alkyl,C₁-C₃ alkoxy-C₁-C₆ alkyl, and —C₁-C₆ alkyl-NR^(J1)R^(J2), wherein R^(J1)and R^(J2) are each independently hydrogen or C₁-C₃ alkyl.60C. The compound of embodiment 59C, or a pharmaceutically acceptablesalt thereof, wherein R^(4a) is selected from the group consisting of—C(CH₃)₂CH₂OH, —CH₂CH₂OH, —C(CH₃)₂CH₂OCH₃, —CH(CH₃)CH₂OH,—CH₂CH₂N(CH₃)₂, —CH₂CF₃.56B. The compound of any one of embodiments 35B-38B, or apharmaceutically acceptable salt thereof, wherein R^(4a) is selectedfrom the group consisting of —C(CH₃)₂CH₂OH, —CH₂CH₂OH, and—C(CH₃)₂CH₂OCH₃.61C. The compound of embodiment 59C, 60C, or 56B, or a pharmaceuticallyacceptable salt thereof, wherein R^(4a) is —C(CH₃)₂CH₂OH.57B. The compound of any one of embodiments 35B-38B, or apharmaceutically acceptable salt thereof, wherein R^(4a) and R^(4b)taken together with the atom to which each is attached form a 5- to10-membered monocyclic, fused bicyclic, or bridged bicyclicheterocyclyl, optionally substituted with one or two substituents, eachindependently selected from the group consisting of halogen, C₁-C₆alkyl, halo-C₁-C₃ alkyl, hydroxy, and C₁-C₃ alkoxy.63C. The compound of embodiment 57B, or a pharmaceutically acceptablesalt thereof, wherein R^(4a) and R^(4b) taken together with the atom towhich each is attached form a piperidinyl, morpholinyl, pyrrolidinyl,azepanyl, indolinyl, azabicyclo[3.1.1]heptanyl,2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, or piperazinyl, optionallysubstituted with one or two substituents, each independently selectedfrom the group consisting of hydroxy, methyl, fluoro, and methoxy.58B. The compound of embodiment 57B or 63C, or a pharmaceuticallyacceptable salt thereof, wherein R^(4a) and R^(4b) taken together withthe atom to which each is attached form a piperidinyl, morpholinyl,pyrrolidinyl, azepanyl, indolinyl, azabicyclo[3.1.1]heptanyl, orpiperazinyl, optionally substituted with one or two substituents, eachindependently selected from the group consisting of methyl, fluoro, andmethoxy.64C. The compound of embodiment 63C or 58B, or a pharmaceuticallyacceptable salt thereof, wherein R^(4a) and R^(4b) taken together withthe atom to which each is attached form a

59B. The compound of embodiment 58B or 64C, or a pharmaceuticallyacceptable salt thereof, wherein R^(4a) and R^(4b) taken together withthe atom to which each is attached form a

60B. The compound of any one of embodiments 35B, 39B-56B, 42C, 43C, 52C,53C, 54C, 55C, 59C, 60C, or 61C, or a pharmaceutically acceptable saltthereof, wherein R^(4b) and R^(4c) taken together with the atom to whicheach is attached form a 5- to 7-membered monocyclic heterocyclyl,optionally substituted with one or two substituents, each independentlyselected from C₁-C₃ alkyl.61B. The compound of embodiment 60B, or a pharmaceutically acceptablesalt thereof, wherein R^(4b) and R^(4c) taken together with the atom towhich each is attached form a piperidin-2-one or a pyrrolidine-2-one,optionally substituted one or two times with methyl.62B. The compound of any one of embodiments 1B-30B, 1C, 5C, 9C, 10C,11C, 12C, 13C, 14C, 15C, 16C, or 31C, or a pharmaceutically acceptablesalt thereof, wherein R⁴ is

wherein R^(4g) is selected from the group consisting of C₆-C₁₀monocyclic or fused bicyclic aryl and C₁-C₃ alkyl.63B. The compound of claim 62B, or a pharmaceutically acceptable saltthereof, wherein R^(4g) is selected from the group consisting of phenyland methyl.64B. The compound of claim any one of embodiments 1B-28B, 1C, 5C, 9C,10C, 11C, 12C, 13C, 14C, 15C, 16C, or 31C, or a pharmaceuticallyacceptable salt thereof, wherein R³ and R⁴ taken together with thenitrogen atom to which each is attached form a 7-membered monocyclic orbridged bicyclic heterocyclyl containing one or two heteroatoms;

-   -   wherein when said 7-membered heterocyclyl contains one        heteroatom, said heterocyclyl is optionally substituted with        one, two, or three substituents, each independently selected        from the group consisting of oxo, halogen, hydroxy, C₁-C₃        alkoxy, cyano, and C₁-C₃ alkyl; and    -   when said 7-membered heterocyclyl contains two heteroatoms, said        heteroatoms are each independently N or O, and said heterocyclyl        is optionally substituted with one, two, or three substituents,        each independently selected from the group consisting of C₁-C₃        alkyl, cyano, oxo, halogen, halo-C₁-C₃ alkyl, and C₆-C₁₀        monocyclic or fused bicyclic aryl; and    -   wherein said aryl is optionally substituted with one or two        substituents, each individually selected from the group        consisting of C₁-C₃ alkoxy, hydroxy, halogen, and C₁-C₃ alkyl.        65B. The compound of embodiment 64B, or a pharmaceutically        acceptable salt thereof, wherein R³ and R⁴ taken together with        the nitrogen atom to which each is attached form a 7-membered        heterocyclyl containing one heteroatom, wherein said        heterocyclyl is optionally substituted once with methyl or oxo;        or, a 7-membered monocyclic or bridged bicyclic heterocyclyl        containing two heteroatoms, wherein said heteroatoms are N or O,        and said heterocyclyl is optionally substituted with one or two        substituents, each independently selected from the group        consisting of phenyl, methyl, and oxo, and wherein said phenyl        is optionally substituted with methoxy.        66B. The compound of embodiment 65B, or a pharmaceutically        acceptable salt thereof, wherein R³ and R⁴ taken together with        the nitrogen atom to which each is attached form a

67B. The compound of any one of embodiments 1B-28B, 1C, 5C, 9C, 1° C.,11C, 12C, 13C, 14C, 15C, 16C, or 31C, or a pharmaceutically acceptablesalt thereof, wherein R³ and R⁴ taken together with the nitrogen atom towhich each is attached form a 10- or 11-membered fused bicyclicheterocyclyl containing one heteroatom, or a 12-membered bicyclic fusedand bridged heterocyclyl, each optionally substituted with one, two, orthree substituents, each independently selected from the groupconsisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxy, and halogen.68B. The compound of embodiment 67B, or a pharmaceutically acceptablesalt thereof, wherein R³ and R⁴ taken together with the nitrogen atom towhich each is attached form a

69B. The compound of any one of embodiments 1B-28B, 1C, 8C, 9C, 10C,11C, 12C, 13C, 14C, 15C, 16C, or 31C, or a pharmaceutically acceptablesalt thereof, wherein R³ and R⁴ taken together with the nitrogen atom towhich each is attached form a 4- or 6-membered monocyclic heterocyclylcontaining one heteroatom; wherein,

said 4-membered monocyclic heterocyclyl is optionally substituted with—(CH₂)_(s)C(═O)NR^(k)R^(l); wherein,

-   -   s is 0, 1, or 2;    -   R^(k) is hydrogen or C₁-C₃ alkyl; and    -   R^(l) is selected from the group consisting of hydrogen, methyl,        phenyl, cyclopentyl, and cyclohexyl;        and,

said 6-membered monocyclic heterocyclyl is optionally substituted withone or two substituents, each independently selected from the groupconsisting of C₁-C₃ alkoxy, oxo, halogen, cyano, and —NR^(q)R^(w);wherein,

-   -   R^(q) is hydrogen or C₁-C₃ alkyl;    -   R^(w) is C₆-C₁₀ monocyclic or fused bicyclic aryl or C₃-C₇        cycloalkyl,        -   wherein said aryl or cycloalkyl is optionally substituted            with one or two substituents, each independently selected            from the group consisting of halogen, C₁-C₃ alkyl, hydroxy,            and C₁-C₃ alkoxy.            70B. The compound of embodiment 69B, or a pharmaceutically            acceptable salt thereof, wherein R³ and R⁴ taken together            with the nitrogen atom to which each is attached form a

71B. The compound of any one of embodiments 1B-70B, 1C, 5C, 9C, 10C,11C, 12C, 13C, 14C, 15C, 16C, 31C, 33C, 35C, 36C, 42C, 52C, 53C, 54C,55C, 61C, 63C, or 64C, or a pharmaceutically acceptable salt thereof,wherein R^(x), in each instance, is methyl.72B. The compound of any one of embodiments 1B-71B, 1C, 5C, 9C, 1° C.,11C, 12C, 13C, 14C, 15C, 16C, 31C, 33C, 35C, 36C, 42C, 52C, 53C, 54C,55C, 61C, 63C, or 64C, or a pharmaceutically acceptable salt thereof,wherein m is 0.73B. The compound of any one of embodiments 1B-71B, 1C, 5C, 9C, 1° C.,11C, 12C, 13C, 14C, 15C, 16C, 31C, 33C, 35C, 36C, 42C, 52C, 53C, 54C,55C, 61C, 63C, or 64C, or a pharmaceutically acceptable salt thereof,wherein m is 2.79C. The compound of claim 1, or a pharmaceutically acceptable saltthereof; wherein,

Z is N;

p is 1;

f is 1;

Y¹, Y², Y³, and Y⁴ are each independently selected from the groupconsisting of CH, N, and C—R⁶, provided that 1 or 2 of Y¹, Y², Y³, andY⁴ can be N;

R⁶, in each instance, is selected from the group consisting of halogen,hydroxy, C₁-C₃ alkoxy, C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃ alkyl,hydroxy-C₁-C₁₀ alkoxy, hydroxy-C₁-C₁₀-alkyl, cyano, —NR^(G)R^(H),halo-C₁-C₃ alkoxy, —O—(C₁-C₆ alkyl)-R^(bb), —O—R^(bb), —(C₁-C₆alkyl)-NR^(GI)R^(HI), halo-C₁-C₃ alkyl, —O—R^(cc)—O—R^(dd), 5- to7-membered monocyclic heteroaryl, and C₃-C₆ cycloalkyl; wherein,

the alkyl moiety in hydroxy-C₁-C₁₀ alkoxy or —O—(C₁-C₆ alkyl)-R^(bb) isoptionally substituted with hydroxy, hydroxy-C₁-C₃-alkyl, halogen, orC₁-C₃ alkoxy;

R^(bb) is 4- to 7-membered monocyclic heterocyclyl, C₃-C₇ cycloalkyl, or—NR^(G)R^(H);

R^(cc) and R^(dd) are each independently C₁-C₃ alkyl;

-   -   wherein, said cycloalkyl, heterocyclyl, or heteroaryl of R⁶ or        R^(bb) is optionally substituted with one or two substituents,        each independently selected from the group consisting of        hydroxy, C₁-C₃ alkoxy, and C₁-C₃ alkyl;

and,

-   -   R^(G1) and R^(H1) are each independently hydrogen or C₁-C₃        alkyl;    -   R^(G) and R^(H) are each independently hydrogen, —C(O)R^(Ga), or        optionally deuterated C₁-C₃ alkyl; wherein,        -   R^(Ga) is C₁-C₃ alkyl or hydrogen;            or,

two R⁶ groups, taken together with the atom to which each is attached,form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, aC₄-C₇ cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5-to 6-membered monocyclic heteroaryl fused with Ring B; wherein,

said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring Bis optionally substituted with one or two substituents, eachindependently selected from the group consisting of C₁-C₃ alkoxy,hydroxy, hydroxy-C₁-C₃-alkyl, C₁-C₃ alkyl, C₃-C₇ cycloalkyl, and 5- or6-membered monocyclic heterocyclyl;

n is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, phenyl, —CH₂CH₂OH,and optionally deuterated methyl or ethyl;

R⁴ is

wherein,

-   -   R^(4c) is selected from the group consisting of hydrogen,        methyl, isopropyl, —CH₂OH, —CH₂OC(CH₃)₃, and —CH₂CH₂SCH₃;    -   R^(4d) is selected from the group consisting of hydrogen and        methyl;

or,

-   -   R^(4c) and R^(4d) taken together with the atom to which each is        attached form a cyclopropyl ring;    -   R^(4b) is hydrogen or methyl;    -   R^(4a) is selected from the group consisting of hydrogen, C₁-C₁₀        alkyl, hydroxy-C₁-C₆ alkyl, C₁-C₃ alkoxy-C₁-C₆ alkyl, —C₁-C₆        alkyl-NR^(J1)R^(J2), C₃-C₇ cycloalkyl, 5- to 10-membered        monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl,        C₆-C₁₀ monocyclic or fused bicyclic aryl, 4- to 10-membered        monocyclic or fused bicyclic heteroaryl, (C₆-C₁₀ monocyclic or        fused bicyclic aryl)-C₁-C₃ alkyl, and (5- to 10-membered        monocyclic or fused bicyclic heteroaryl)-C₁-C₃ alkyl; wherein        the cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or        heteroaryl-alkyl of R^(4a) is optionally substituted with one,        two, or three substituents, each independently selected from the        group consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl,        hydroxy, C₁-C₃ alkoxy, halo-C₁-C₃ alkoxy, oxo, C₃-C₇ cycloalkyl,        and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl;        -   R^(J1) and R^(J2) are independently hydrogen or C₁-C₃ alkyl;

or,

-   -   R^(4a) and R^(4b) taken together with the atom to which each is        attached form a 5- to 10-membered monocyclic, fused bicyclic, or        bridged bicyclic heterocyclyl, optionally substituted with one        or two substituents, each independently selected from the group        consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl, hydroxy,        and C₁-C₃ alkoxy;

R^(x), in each instance, is C₁-C₃ alkyl; and

m is 0, 1, or 2.

74B. The compound of embodiment 1B, or a pharmaceutically acceptablesalt thereof, wherein,

Z is N;

p is 1;

f is 1;

Y¹, Y², Y³, and Y⁴ are each independently selected from the groupconsisting of CH, N, and C—R⁶, provided that 1 or 2 of Y¹, Y², Y³, andY⁴ can be N;

R⁶, in each instance, is selected from the group consisting of halogen,hydroxy, C₁-C₃ alkoxy, C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃ alkyl,hydroxy-C₁-C₆ alkoxy, hydroxy-C₁-C₃ alkyl, cyano, —NR^(G)R^(H),halo-C₁-C₃ alkoxy, —O—(CH₂)_(u)—R^(bb), halo-C₁-C₃ alkyl,—O—R^(cc)—O—R^(dd), 5- to 7-membered monocyclic heteroaryl, and C₃-C₆cycloalkyl; wherein,

u is an integer from 0 to 6;

R^(bb) is 4- to 7-membered monocyclic heterocyclyl, C₃-C₇ cycloalkyl, or—NR^(G)R^(H);

R^(cc) and R^(dd) are each independently C₁-C₃ alkyl;

-   -   wherein, said cycloalkyl, heterocyclyl, or heteroaryl is        optionally substituted with one or two substituents, each        independently selected from the group consisting of hydroxy,        C₁-C₃ alkoxy, and C₁-C₃ alkyl;

and,

-   -   R^(G) and R^(H) are each independently hydrogen, —C(O)R^(Ga), or        C₁-C₃ alkyl; wherein,        -   R^(Ga) is C₁-C₃ alkyl or hydrogen;            or,

two R⁶ groups, taken together with the atom to which each is attached,form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, aC₄-C₇ cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5-to 6-membered monocyclic heteroaryl fused with Ring B; wherein,

said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring Bis optionally substituted with one or two substituents, eachindependently selected from the group consisting of C₁-C₃ alkoxy,hydroxy, hydroxy-C₁-C₃-alkyl, C₁-C₃ alkyl, C₃-C₇ cycloalkyl, and 5- or6-membered monocyclic heterocyclyl;

n is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, methyl, ethyl,phenyl, and —CH₂CH₂OH;

R⁴ is

wherein,

-   -   R^(4c) is selected from the group consisting of hydrogen,        methyl, isopropyl, —CH₂OH, —CH₂OC(CH₃)₃, and —CH₂CH₂SCH₃;    -   R^(4d) is selected from the group consisting of hydrogen and        methyl;

or,

-   -   R^(4c) and R^(4d) taken together with the atom to which each is        attached form a cyclopropyl ring;    -   R^(4b) is hydrogen or methyl;    -   R^(4a) is selected from the group consisting of hydrogen, C₁-C₆        alkyl, hydroxy-C₁-C₆ alkyl, C₁-C₃ alkoxy-C₁-C₆ alkyl, C₃-C₇        cycloalkyl, 5- to 10-membered monocyclic, fused bicyclic, or        bridged bicyclic heterocyclyl, C₆-C₁₀ monocyclic or fused        bicyclic aryl, 5- to 10-membered monocyclic or fused bicyclic        heteroaryl, (C₆-C₁₀ monocyclic or fused bicyclic aryl)-C₁-C₃        alkyl, and (5- to 10-membered monocyclic or fused bicyclic        heteroaryl)-C₁-C₃ alkyl; wherein the cycloalkyl, heterocyclyl,        aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl of R^(4a) is        optionally substituted with one, two, or three substituents,        each independently selected from the group consisting of        halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl, hydroxy, C₁-C₃ alkoxy,        halo-C₁-C₃ alkoxy, halo-C₁-C₃ alkyl, oxo, C₃-C₇ cycloalkyl, and        5- to 10-membered monocyclic or fused bicyclic heterocyclyl;

or,

-   -   R^(4a) and R^(4b) taken together with the atom to which each is        attached form a 5- to 10-membered monocyclic, fused bicyclic, or        bridged bicyclic heterocyclyl, optionally substituted with one        or two substituents, each independently selected from the group        consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl, hydroxy,        and C₁-C₃ alkoxy;

R^(x), in each instance, is C₁-C₃ alkyl; and

m is 0, 1, or 2.

75B. The compound of embodiment 74B or 79C, or a pharmaceuticallyacceptable salt thereof, wherein m is 0.

76B. The compound of embodiment 74B or 79C, or a pharmaceuticallyacceptable salt thereof, wherein m is 2 and R^(X), in each instance, ismethyl.

77B. The compound of any one of embodiments 74B-76B or 79C, or apharmaceutically acceptable salt thereof, wherein, Y¹, Y², Y³, and Y⁴are each CH or C—R⁶;

Y³ is N and Y¹, Y², and Y⁴ are each CH or C—R⁶;

Y² is N and Y¹, Y³, Y⁴ are each CH or C—R⁶;

or

Y¹ is N and Y², Y³, and Y⁴ are each CH or C—R⁶.

77bb. The compound of any one of embodiments 74B-77B or 79C, or apharmaceutically acceptable salt thereof, wherein, Y¹ is CH, Y² is C—R⁶,Y³ is CH, and Y⁴ is CH.

83C. The compound of any one of embodiments 79C or 75B-77bb, or apharmaceutically acceptable salt thereof; wherein R⁶, in each instance,is selected from the group consisting of halogen, hydroxy, C₁-C₃ alkoxy,C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃ alkyl, hydroxy-C₁-C₆ alkoxy,hydroxy-C₁-C₁₀-alkyl, —O—R^(bb), —O—(C₁-C₆ alkyl)-R^(bb), halo-C₁-C₃alkoxy, —O—R^(cc)—O—R^(dd), halo-C₁-C₃ alkyl, C₃- C₆ cycloalkyl, and—NR^(G)R^(H); wherein,

R^(bb) is —NR^(G)R^(H), 4- to 6-membered monocyclic heterocyclyl, orC₃-C₇ cycloalkyl;

R^(G) and R^(H) are each independently hydrogen or C₁-C₃ alkyl;

R^(cc) and R^(dd) are each independently C₁-C₃ alkyl; and, wherein,

said cycloalkyl or heterocyclyl of R⁶ or R^(bb) is optionallysubstituted with one or two substituents, each independently selectedfrom the group consisting of hydroxy, C₁-C₃ alkoxy, and C₁-C₃ alkyl.

84C. The compound of embodiment 83C, wherein R^(bb) is selected from thegroup consisting of cyclopropyl, cyclobutyl, tetrahydrofuranyl,oxetanyl, morpholinyl, and pyrrolidinyl, each optionally substitutedwith hydroxy or methyl; or, R^(bb) is —N(CH₃)₂.

78B. The compound of any one of embodiments 74B-77B, or apharmaceutically acceptable salt thereof; wherein R⁶, in each instance,is selected from the group consisting of halogen, hydroxy, C₁-C₃ alkoxy,C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃ alkyl, hydroxy-C₁-C₆ alkoxy,hydroxy-C₁-C₃ alkyl, —O—(CH₂)_(u)—R^(bb), halo-C₁-C₃ alkoxy,—O—R^(cc)—O—R^(dd), halo-C₁-C₃ alkyl, C₃-C₆ cycloalkyl, and—NR^(G)R^(H); wherein,

R^(bb) is —NR^(G)R^(H), 4- or 5-membered monocyclic heterocyclyl, orC₃-C₇ cycloalkyl;

u is an integer from 0 to 3;

R^(G) and R^(H) are each independently hydrogen or C₁-C₃ alkyl;

R^(cc) and R^(dd) are each independently C₁-C₃ alkyl; and, wherein,

said cycloalkyl or heterocyclyl is optionally substituted with one ortwo substituents, each independently selected from the group consistingof hydroxy, C₁-C₃ alkoxy, and C₁-C₃ alkyl.

79B. The compound of embodiment 78B, wherein R^(bb) is selected from thegroup consisting of cyclopropyl, cyclobutyl, tetrahydrofuranyl,oxetanyl, and pyrrolidinyl, each optionally substituted with hydroxy ormethyl.

85C. The compound of any one of embodiments 79C, 75B-77B, or 84C, or apharmaceutically acceptable salt thereof, wherein R⁶, in each instance,is selected from the group consisting of methoxy, ethoxy, methyl,fluoro, chloro, ethyl, —N(CH₃)₂, hydroxy, —OCH₂CH(CH₃)OH,—OCH₂CH₂N(CH₂CH₃)₂, —OCH₂C(CH₃)(CH₂CH₃)OH, —OCH₂CH(CH₂OC H₃)OH,—OCH₂CH₂OH, —CH₂OH, —CH₂OCH₃, —OCH₂CH₂NH₂, —OCH₂CH₂N(CH₃)₂,—OCH₂C(CH₃)₂OH, —OCH₂CF₃, —OCHF₂, —OCF₃, —OCH₂CH₂OCH₃, —OCH₂CH₂F,—OC(CH₃)₂CH₂OH, —CH₂CH₂OH,

where

indicates the point of attachment to Ring B.80B. The compound of any one of embodiments 74B-79B, or apharmaceutically acceptable salt thereof, wherein R⁶, in each instance,is selected from the group consisting of methoxy, ethoxy, methyl,fluoro, chloro, ethyl, —N(CH₃)₂, hydroxy, —OCH₂CH₂OH, —CH₂OH, —CH₂OCH₃,—OCH₂CH₂NH₂, —OCH₂CH₂N(CH₃)₂, —OCH₂C(CH₃)₂O H, —OCH₂CF₃, —OCHF₂, —OCF₃,—OCH₂CH₂OCH₃, —OCH₂CH₂F, —OC(CH₃)₂CH₂OH, —CH₂CH₂OH,

where

indicates the point of attachment to Ring B.86C. The compound of embodiment 85C, or a pharmaceutically acceptablesalt thereof, wherein R⁶, in each instance, is methoxy, —OCH₂CH₂OH,—OCH₂CH₂N(CH₃)₂, —OCH₂C(CH₃)₂OH,

87C. The compound of embodiment 86C, or a pharmaceutically acceptablesalt thereof, wherein R⁶, in each instance, is methoxy, —OCH₂CH₂N(CH₃)₂,—OCH₂C(CH₃)₂OH,

81B. The compound of embodiment 80B or 86C, or a pharmaceuticallyacceptable salt thereof, wherein R⁶, in each instance is methoxy,—OCH₂CH₂OH, —OCH₂CH₂N(CH₃)₂, —OCH₂C(CH₃)₂OH, or

82B. The compound of any one of embodiments 74B-77B, or apharmaceutically acceptable salt thereof, wherein two R⁶ groups, takentogether with the atom to which each is attached, form a pyrazolyl,dioxanyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, dioxolanyl, orphenyl ring fused with Ring B, wherein said ring is optionallysubstituted with one substituent selected from the group consisting ofhydroxy, methoxy, tetrahydropyranyl, —CH₂OH, and methyl.83B. The compound of any one of embodiments 74B-82B, 79C, 83C, 84C, 85C,86C, or 87C, or a pharmaceutically acceptable salt thereof, wherein R³is methyl.84B. The compound of any one of embodiments 74B-82B, 79C, 83C, 84C, 85C,86C, or 87C, or a pharmaceutically acceptable salt thereof, wherein n is1.85B. The compound of any one of embodiments 74B-84B, 79C, 83C, 84C, 85C,86C, or 87C, or a pharmaceutically acceptable salt thereof, whereinR^(4c) is hydrogen.92C. The compound of any one of embodiments 79C, 83C, 84C, 85C, 86C, or87C, or a pharmaceutically acceptable salt thereof, wherein R^(4a) isselected from the group consisting of.

i. tert-butyl or isopropyl;

ii. phenyl optionally substituted with one substituent selected from thegroup consisting of fluoro, chloro, methyl, and methoxy;

iii. pyridinyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyridizinyl, orquinolinyl, optionally substituted with one substituent selected fromthe group consisting of fluoro, chloro, methoxy, azepanyl, cyclopropyl,—CF₃, —OCF₃, and methyl;

iv. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andbicyclo[1.1.1]pentan-1-yl, optionally substituted with one or twosubstituents, each independently selected from the group consisting ofmethyl, —CF₃, fluoro, and hydroxy;

v. tetrahydrofuranyl, pyrrolidinyl, benzo[d][1,3]dioxolyl, andtetrahydropyranyl, optionally substituted with one or two substituents,each independently selected from the group consisting of methyl,methoxy, and oxo;

vi. benzyl, 2-(1-cyclobutyl-5-methyl-1H-imidazol-2-yl)ethyl, andpyridinyl-methyl; and

vii. —C(CH₃)₂CH₂OH, —CH₂CH₂OH, and —C(CH₃)₂CH₂OCH₃.

86B. The compound of any one of embodiments 74B-84B, 79C, 83C, 84C, 85C,86C, or 87C, or a pharmaceutically acceptable salt thereof, whereinR^(4a) is selected from the group consisting of.

i. tert-butyl;

ii. phenyl optionally substituted with one substituent selected from thegroup consisting of fluoro, chloro, methyl, and methoxy;

iii. pyridinyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyridizinyl, orquinolinyl, optionally substituted with one substituent selected fromthe group consisting of fluoro, chloro, methoxy, azepanyl, cyclopropyl,—CF₃, —OCF₃, or methyl;

iv. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andbicyclo[1.1.1]pentan-1-yl, optionally substituted with one or twosubstituents, each independently selected from the group consisting ofmethyl, —CF₃, fluoro, or hydroxy;

v. tetrahydrofuranyl, pyrrolidinyl, benzo[d][1,3]dioxolyl, andtetrahydropyranyl, optionally substituted with one or two substituents,each independently selected from the group consisting of methyl,methoxy, and oxo;

vi. phenyl-methyl, 1-cyclobutyl-2-ethyl-5-methyl-1H-imidazolyl, andpyridinyl-methyl; and

vii. —C(CH₃)₂CH₂OH, —CH₂CH₂OH, and —C(CH₃)₂CH₂OCH₃.

87B. The compound of any one of embodiments 74B-84B, 79C, 83C, 84C, 85C,86C, or 87C, wherein R^(4a) and R^(4b) taken together with the atom towhich each is attached form a piperidinyl, morpholinyl, pyrrolidinyl,azepanyl, indolinyl, azabicyclo[3.1.1]heptanyl, or piperazinyl,optionally substituted with one or two substituents, each independentlyselected from the group consisting of methyl, fluoro, and methoxy.88B. The compound of embodiment 1B or 1C, or a pharmaceuticallyacceptable salt thereof, wherein,

Z is N;

f is 1;

R⁶, in each instance, is selected from the group consisting of C₁-C₃alkyl, —NR^(G)R^(H), halogen, and C₁-C₃ alkoxy;

p is 1

n is 0 or 1

R^(G) and R^(H) are each independently hydrogen or C₁-C₃ alkyl;

Y¹, Y², Y³, and Y⁴ are each independently selected from the groupconsisting of CH, N, and C—R⁶, provided that 1 or 2 of Y¹, Y², Y³, andY⁴ can be N;

R^(x), in each instance, is halogen, C₁-C₆ alkyl, C₁-C₃ alkoxy, hydroxy,or cyano;

m is 0; and

R³ and R⁴ taken together with the nitrogen atom to which each isattached form a:

-   -   i. 7-membered fused bicyclic heterocyclyl, 7-membered bridged        bicyclic heterocyclyl, or 7-membered monocyclic heterocyclyl        containing one or two heteroatoms;        -   wherein when said 7-membered monocyclic heterocyclyl            contains one heteroatom, said heterocyclyl is optionally            substituted with one, two, or three substituents, each            independently selected from the group consisting of oxo,            halogen, hydroxy, C₁-C₃ alkoxy, cyano, and C₁-C₃ alkyl; and,        -   when said 7-membered monocyclic heterocyclyl contains two            heteroatoms, said heteroatoms are each independently N or O,            and said heterocyclyl is optionally substituted with one,            two, or three substituents, each independently selected from            the group consisting of C₁-C₃ alkyl, cyano, oxo, halogen,            halo-C₁-C₃ alkyl, and C₆-C₁₀ monocyclic or fused bicyclic            aryl; and            -   wherein said aryl is optionally substituted with one or                two substituents, each individually selected from the                group consisting of C₁-C₃ alkoxy, hydroxy, halogen, and                C₁-C₃ alkyl;    -   ii. 4- or 6-membered monocyclic heterocyclyl containing one        heteroatom;        -   wherein said 4-membered monocyclic heterocyclyl is            optionally substituted with one or two substituents, each            independently selected from the group consisting of halogen,            C₁-C₃ alkoxy, oxo, and —(CH₂)_(s)C(═O)NR^(k)R^(l); wherein,            -   s is 0, 1, 2, or 3;            -   R^(k) is hydrogen or C₁-C₃ alkyl; and            -   R^(l) is selected from the group consisting of hydrogen,                hydroxy, C₁-C₃ alkyl, C₃-C₇ cycloalkyl, and C₆-C₁₀                monocyclic or fused bicyclic aryl;        -   wherein said 6-membered monocyclic heterocyclyl is            optionally substituted with one or two substituents, each            independently selected from the group consisting of C₁-C₃            alkoxy, oxo, halogen, cyano, and NR^(q)R^(w); wherein,            -   R^(q) is hydrogen or C₁-C₃ alkyl; and            -   R^(w) is C₆-C₁₀ monocyclic or bicyclic aryl or C₃-C₇                cycloalkyl, wherein said aryl or cycloalkyl is                optionally substituted with one or two substituents,                each independently selected from the group consisting of                halogen, C₁-C₃ alkyl, hydroxy, and C₁-C₃ alkoxy;

or,

-   -   iii. 8-, 9-, 10- or 11-membered fused bicyclic heterocyclyl, or        12-membered bicyclic bridged, fused heterocyclyl, wherein said        8-, 9-, or 11-membered heterocyclyl contains one heteroatom and        said 10- or 12-membered heterocyclyl contains one or two        heteroatoms; and wherein said 10-, 11-, or 12-membered        heterocyclyl is optionally substituted with one, two, or three        substituents, each independently selected from the group        consisting of halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy, and hydroxy.        89B. The compound of embodiment 88B, or a pharmaceutically        acceptable salt thereof, wherein Y¹, Y², Y³, and Y⁴ are each CH        or C—R⁶.        90B. The compound of embodiment 88B or 89B, or a        pharmaceutically acceptable salt thereof, wherein R⁶, if        present, is selected from the group consisting of —N(CH₃)₂,        methyl, methoxy, fluoro, and chloro.        91B. The compound of any one of embodiments 88B-90B, or a        pharmaceutically acceptable salt thereof, wherein R³ and R⁴        taken together with the nitrogen atom to which each is attached        form a 7-membered heterocyclyl containing one heteroatom,        wherein said heterocyclyl is optionally substituted once with        methyl or oxo; or, a 7-membered monocyclic or bridged bicyclic        heterocyclyl containing two heteroatoms, wherein said        heteroatoms are N or O, and said heterocyclyl is optionally        substituted with one or two substituents, each independently        selected from the group consisting of phenyl, methyl, and oxo,        and wherein said phenyl is optionally substituted with methoxy.        92B. The compound of any one of embodiments 88B-90B, or a        pharmaceutically acceptable salt thereof, wherein R³ and R⁴        taken together with the nitrogen atom to which each is attached        form a 10- or 11-membered fused bicyclic heterocyclyl containing        one heteroatom, or a 12-membered bicyclic fused, bridged        heterocyclyl, each optionally substituted with one, two, or        three substituents, each independently selected from the group        consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxy, and halogen.        93B. The compound of any one of embodiments 88B-90B, or a        pharmaceutically acceptable salt thereof, wherein R³ and R⁴        taken together with the nitrogen atom to which each is attached        form a 4- or 6-membered monocyclic heterocyclyl containing one        heteroatom; wherein,

said 4-membered monocyclic heterocyclyl is optionally substituted with—(CH₂)_(s)C(═O)NR^(k)R^(l); wherein,

-   -   s is 0, 1, or 2;    -   R^(k) is hydrogen or C₁-C₃ alkyl; and    -   R^(l) is selected from the group consisting of hydrogen, methyl,        phenyl, cyclopentyl, and cyclohexyl;        and,

said 6-membered monocyclic heterocyclyl is optionally substituted withone or two substituents, each independently selected from the groupconsisting of C₁-C₃ alkoxy, oxo, halogen, cyano, and NR^(q)R^(w);wherein,

-   -   R^(q) is hydrogen or C₁-C₃ alkyl;    -   R^(w) is C₆-C₁₀ monocyclic or fused bicyclic aryl or C₃-C₇        cycloalkyl, wherein said aryl or cycloalkyl is optionally        substituted with one or two substituents, each independently        selected from the group consisting of halogen, C₁-C₃ alkyl,        hydroxy, and C₁-C₃ alkoxy.        94B. The compound of embodiment 1B, 74B, or 1C, or a        pharmaceutically acceptable salt thereof, wherein,

Z is N;

p is 1;

f is 1;

Y¹, Y², Y³, and Y⁴ are each independently CH or C—R⁶.

R⁶, in each instance, is selected from the group consisting of C₁-C₃alkyl, hydroxy, C₁-C₃ alkoxy, C₁-C₃ alkoxy-C₁-C₃ alkyl, hydroxy-C₁-C₃alkyl, hydroxy-C₁-C₆ alkoxy, —O—(CH₂)_(u)—R^(bb), halo-C₁-C₃ alkyl,—O—R^(cc)—O—R^(dd), and C₃-C₆ cycloalkyl; or, R⁶, in each instance, is—O—R^(bb) or —O—(C₁-C₆ alkoxy)-R^(bb), wherein,

u is an integer from 0 to 6;

R^(bb) is 4- to 7-membered monocyclic heterocyclyl, C₃-C₇ cycloalkyl, or—NR^(G)R^(H);

R^(cc) and R^(dd) are each independently C₁-C₃ alkyl;

wherein, said cycloalkyl or heterocyclyl is optionally substituted withone or two substituents, each independently selected from the groupconsisting of hydroxy, C₁-C₃ alkoxy, and C₁-C₃ alkyl; and,

R^(G) and R^(H) are each independently hydrogen, —C(O)R^(Ga), or C₁-C₃alkyl; wherein,

R^(Ga) is C₁-C₃ alkyl or hydrogen;

n is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, methyl, ethyl,phenyl, and —CH₂CH₂OH;

R⁴ is

wherein,R^(4c) is selected from the group consisting of hydrogen, methyl,isopropyl, —CH₂OH, and —CH₂OC(CH₃)₃;R^(4d) is selected from the group consisting of hydrogen and methyl;

-   -   or,    -   R^(4c) and R^(4d) taken together with the atom to which each is        attached form a cyclopropyl ring;

R^(4b) is hydrogen or methyl;

R^(4a) is selected from the group consisting of hydrogen, C₁-C₆ alkyl,hydroxy-C₁-C₆ alkyl, C₁-C₃ alkoxy-C₁-C₆ alkyl, C₃-C₇ cycloalkyl, 5- to10-membered monocyclic, fused bicyclic, or bridged bicyclicheterocyclyl, C₆-C₁₀ monocyclic or fused bicyclic aryl, 5- to10-membered monocyclic or fused bicyclic heteroaryl, (C₆-C₁₀ monocyclicor fused bicyclic aryl)-C₁-C₃ alkyl, and (5- to 10-membered monocyclicor fused bicyclic heteroaryl)-C₁-C₃ alkyl; wherein the cycloalkyl,heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl of R^(4a)is optionally substituted with one, two, or three substituents, eachindependently selected from the group consisting of halogen, C₁-C₆alkyl, halo-C₁-C₃ alkyl, hydroxy, C₁-C₃ alkoxy, halo-C₁-C₃ alkoxy,halo-C₁-C₃ alkyl, oxo, C₃-C₇ cycloalkyl, and 5- to 10-memberedmonocyclic or fused bicyclic heterocyclyl;

or,

R^(4a) and R^(4b) taken together with the atom to which each is attachedform a 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclicheterocyclyl, optionally substituted with one or two substituents, eachindependently selected from the group consisting of halogen, C₁-C₆alkyl, halo-C₁-C₃ alkyl, hydroxy, and C₁-C₃ alkoxy;

R^(x), in each instance, is C₁-C₃ alkyl; and

m is 0, 1, or 2.

95B. The compound of embodiment 94B, or a pharmaceutically acceptablesalt thereof, wherein, Y¹ is CH, Y² is C—R⁶, Y³ is CH, and Y⁴ is CH.

96B. The compound of embodiment 94B or 95B, or a pharmaceuticallyacceptable salt thereof, wherein R⁶ is selected from the groupconsisting of hydroxy-C₁-C₆ alkoxy, and —O—(CH₂)_(u)—R^(bb); wherein,

u is an integer from 0 to 6;

R^(bb) is 4- to 7-membered monocyclic heterocyclyl, C₃-C₇ cycloalkyl, or—NR^(G)R^(H);

wherein, said cycloalkyl or heterocyclyl is optionally substituted withone or two substituents, each independently selected from the groupconsisting of hydroxy, C₁-C₃ alkoxy, and C₁-C₃ alkyl; and,

R^(G) and R^(H) are each independently hydrogen or C₁-C₃ alkyl; and

n is 0, 1, or 2.

97B. The compound of embodiment 96B, or a pharmaceutically acceptablesalt thereof, wherein R⁶ is selected from the group consisting of

—OCH₂CH₂OH, —OCH₂CH₂N(CH₃)₂, —OCH₂C(CH₃)₂OH, and

98B. The compound of any one of embodiments 94B-97B, or apharmaceutically acceptable salt thereof, wherein:

R³ is methyl;

R^(4c) and R^(4d) are each hydrogen;

R^(4b) is hydrogen; and,

R^(4a) is selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀monocyclic or fused bicyclic aryl, and 5- to 10-membered monocyclic orfused bicyclic heteroaryl, optionally substituted with one or twosubstituents, each independently selected from the group consisting ofhalogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl, hydroxy, C₁-C₃ alkoxy, andhalo-C₁-C₃ alkoxy.

99B. The compound of embodiment 98B, or a pharmaceutically acceptablesalt thereof, wherein R^(4a) is selected from the group consisting ofC₁-C₆ alkyl, phenyl, and pyridinyl, wherein said phenyl or pyrimidinylis optionally substituted with C₁-C₃ alkoxy.

100B. The compound of embodiment 99B, or a pharmaceutically acceptablesalt thereof, wherein R^(4a) is selected from the group consisting oftert-butyl and

101B. The compound of embodiment 1A, 1B, or 1C selected from Table 1, ora pharmaceutically acceptable salt thereof.102B. A pharmaceutical composition comprising a compound according toany one of embodiments 1B-101B, 1A-47A, 1C, 5C, 9C, 10C, 11C, 12C, 13C,14C, 15C, 16C, 31C, 33C, 35C, 36C, 42C, 52C, 53C, 54C, 55C, 61C, 63C,64C, 79C, 83C, 84C, 85C, 86C, or 87C, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient.103B. A method of inhibiting iron transport mediated by ferroportin in asubject, comprising administering to the subject an effective amount ofa compound of any one of embodiments 1B-101B, 1A-47A, 1C, 5C, 9C, 10C,11C, 12C, 13C, 14C, 15C, 16C, 31C, 33C, 35C, 36C, 42C, 52C, 53C, 54C,55C, 61C, 63C, 64C, 79C, 83C, 84C, 85C, 86C, or 87C, or thepharmaceutical composition of embodiment 102B.

The General Procedures and Examples provide exemplary methods forpreparing compounds. Those skilled in the art will appreciate that othersynthetic routes may be used to synthesize the compounds. Althoughspecific starting materials and reagents are depicted and discussed inthe Schemes, General Procedures, and Examples, other starting materialsand reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of theexemplary compounds prepared by the described methods can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

General Synthetic Schemes

General synthetic approaches to FPN1 compounds 1a and 1b. In certainembodiments, compound 1a can be synthesized as shown in Scheme 1, thecore intermediate 2a could be displaced by various substituted amine 3avia method A to give intermediate 4a, which was then coupled withvarious organometallic reagent 5a to provide final compound 1a.Alternatively, final compound 1a could be synthesized as shown in Scheme2. Intermediate 2a could be displaced by primary amine 6a to giveintermediate 7a, after coupling with organometallic reagent 5a, theresulting intermediate 8a could then alkylated by a halide to givecompound 1a. Final compound 1b could be synthesized according to scheme3. Intermediate 2a was displaced by glycinate 9a to provide intermediate10a, after coupling with organometallic reagent 5a, the resultingintermediate 11a was saponified. The corresponding carboxylic acidintermediate 12a was coupled with various amine to form compound 1b.

Modifications and variations to schemes 1-3 can be made based on theavailability of starting materials and synthetic compatibility ofreagents, starting materials, or intermediates. This should be obviousto those who are familiar with the art. For example, R₁ and R₂ could behydrogen, halogen, simple alkyl or could join to form a ring; R₃ couldbe hydrogen or alkyl; R₄ could be alkyl substituted by aminocarbonyl,alkoxy; or R₃ and R₄ could join together to form a cyclic amine. Formethod B, another available heteroaromatic Suzuki or Stille reagentcould be used to provide the final compound 1a.

Scheme 1 depicts a method for preparing exemplary compounds using MethodA and Method B.

Scheme 2 depicts a method for preparing exemplary compounds using MethodA, Method B, and Method C.

Scheme 3 depicts a method for preparing exemplary compounds using MethodA, Method B, Method D, and Method E.

The conditions and reagents for Methods A-E are provided in the belowExamples. The following examples are offered by way of illustration andnot by way of limitation.

1. SYNTHETIC EXAMPLES Example 1.1 Method A: General Synthetic Method forNucleophilic Coupling of Amine to Intermediate 4a

Into a 100-mL round-bottom flask, was placed dichloropyrimidineintermediate 2a (1.00 equiv), CH₃CN, amine 3a (1.10 equiv), andtriethylamine (2.00 equiv). The resulting solution was stirred for 3 hrat 80° C. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether to give intermediate 4a.

Example 1.2 Method B: General Synthetic Method for Metal Mediated CrossCoupling

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed intermediate 4a (1.00 equiv),dioxane, organometallic reagent 5 (2.0 equiv) and Pd(dppf)Cl₂ (0.05equiv). The resulting solution was stirred overnight at 100° C. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:1) orsubjected to preparative HPLC purification to give compound 1a, 8a, or11a.

Example 1.3 Method C: General Synthetic Method for Alkylation withHalide to Give Compound 1a

Intermediate 8a (1.00 eq.) was dissolved in DMF and cooled in an icebath. Sodium hydride (2.00 eq.) (60%) was added in two portions and thereaction was stirred for 45 min. Halide (2.00 eq.) was added slowly andthe mixture was stirred for 1.5 h more. Water (20 ml) and ethyl acetate(100 ml) were added, the phases were separated, and the aqueous phasewas extracted with more ethyl acetate The combined organic phases werewashed with some water and dried over sodium sulfate. After evaporationof solvent, the residue was purified by reverse phase chromatography(Waters XSelect CSH C18 column, 0-70% acetonitrile/0.1% aqueous formicacid gradient). The purified fractions were treated with 1 M HCl andfreeze-dried to give compound 1a.

Example 1.4 Method D: General Synthetic Method for Saponification toGive 12a

Intermediate 11a (1.00 eq.) was dissolved in THE and methanol. Lithiumhydroxide (5.00 eq.) was dissolved in water and was added dropwise tothe solution. After 7 h, the mixture was acidified carefully with 6 MHCl to pH 3 and evaporated to dryness. The residue was co-evaporatedwith toluene and dried under high vacuum to give 12a.

Example 1.5 Method E: General Synthetic Method for Amide Formation toGive 1b

Intermediate 12a (1.00 eq.) was suspended in N,N-dimethylformamide,N,N-Diisopropylethylamine (2.50 eq.), amine (1.35 eq.) and then1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 1.35 eq.) were added. After 40 h,ethyl acetate (50 ml) and sodium bicarbonate solution (20 ml) wereadded, the phases were separated, and the aqueous phase was extractedwith ethyl acetate (50 ml). The combined organic phases were washed withsodium chloride solution and dried over sodium sulfate. Afterevaporation of the solvents, the residue was purified by reverse phasechromatography (Waters XSelect CSH C18 column, 0-70% acetonitrile/0.1%aqueous formic acid gradient) to give compound 1b.

Example 1.6 Experimental Procedures for Common Intermediates

Scheme 4 Depicts a Method for Preparing Intermediate I

Step 1

2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2.00 g; 10.58 mmol;1.00 eq.) was dissolved in acetonitrile (36 ml).(2-Ethoxy-2-oxoethyl)(methyl)azanium chloride (2.11 g; 13.75 mmol; 1.30eq., sarcosine ethyl ester HCl) was added, followed byN,N-diisopropylethylamine (4.6 mL; 26.45 mmol; 2.50 eq.) slowly. Thereaction was stirred at 25° C. for 22 h and then at 50° C. for 20 h. Thesolvent was evaporated and the residue was purified by silica gelchromatography (ethyl acetate/hexanes gradient) to give ethyl2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetate(2.18 g, 76%) as a solid. ¹H NMR (400 MHz, Chloroform-d) δ 4.30-4.19 (m,4H), 3.31 (s, 3H), 3.11 (t, J=7.4 Hz, 2H), 2.88 (t, J=7.9 Hz, 2H),2.12-2.02 (m, 2H), 1.30 (t, J=7.2 Hz, 3H).

Step 2

Ethyl2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetate(900.00 mg; 3.34 mmol; 1.00 eq.) was dissolved in 1,4-dioxane (9 ml) andpurged with argon. 2-(Tributylstannyl)pyridine (2.34 mL; 6.67 mmol; 2.00eq.) and tetrakis(triphenylphosphane) palladium (385.58 mg; 0.33 mmol;0.10 eq.) were added, the reaction vessel was sealed, and then stirredin a heat bath at 105° C. After 16 h, the solvent was evaporated and theresidue was purified by silica gel chromatography(methanol/dichloromethane) to give ethyl2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetate(0.72 g, 62%)¹H NMR (400 MHz, Chloroform-d) δ 8.83 (d, J=4.8 Hz, 1H),8.39-8.28 (m, 1H), 7.86-7.77 (m, 1H), 7.41-7.32 (m, 1H), 4.37 (s, 2H),4.20 (q, J=7.2, 1.5 Hz, 2H), 3.42 (s, 3H), 3.23-3.12 (m, 4H), 2.15-2.07(m, 2H), 1.27-1.23 (m, 3H). MS (ES+): (M+H)⁺=269.9.

Step 3

Ethyl2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetate(0.72 g; 2.30 mmol; 1.00 eq.) was dissolved in THF (20 ml) and methanol(5 ml). Lithium hydroxide (0.28 g; 11.52 mmol; 5.00 eq.) dissolved inwater (8 ml) was added dropwise to the solution. After 7 h, the mixturewas acidified carefully with 6 M HCl to pH 3 and evaporated to dryness.The residue was co-evaporated with toluene and dried under high vacuumto give2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}aceticacid hydrochloride (Intermediate I) as an off-white solid. ¹H NMR (400MHz, DMSO-d6) δ 8.84 (d, J=4.7 Hz, 1H), 8.41 (d, J=7.9 Hz, 1H),8.21-8.12 (m, 1H), 7.75 (dd, J=7.8, 4.8 Hz, 1H), 3.28-3.27 (m, 2H),3.07-3.01 (m, 2H), 2.15-2.05 (m, 2H). MS (ES+): (M+H)⁺=284.9.

Example 1.7

Scheme 5 Depicts a Method for Preparing Intermediate II

Step 1

Into a 1-L 3-necked round-bottom flask was placed2-(benzyloxycarbonylamino)acetic acid (20.0 g, 95.6 mmol, 1.00 equiv),DCM (500 mL), HOBt (15.5 g, 114.7 mmol, 1.20 equiv), EDCI (22.0 g, 114.7mmol, 1.20 equiv), and tert-butylamine (21.0 g, 286.8 mmol, 3.00 equiv).The resulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated. The residue was applied onto asilica gel column with PE/EA ether (0-50%). This resulted in 25.1 g(99%) of benzyl N-[(tert-butylcarbamoyl)methyl]-carbamate as a whitesolid. LCMS: (ES, m/z): [M+H]+265.

Into a 250-mL round-bottom flask, was placed benzylN-[(tert-butylcarbamoyl)methyl]carbamate (7.0 g, 26.48 mmol, 1.00equiv), MeOH (50 mL), and Pd/C (10%) (0.70 g, 10%). The resultingsolution was stirred overnight at room temperature under H₂ (1 atm). Thesolids were filtered out. The resulting mixture was concentrated. Thisresulted in 3.3 g (95%) of 2-amino-N-tert-butylacetamide as a colorlessoil. LCMS: (ES, m/z): [M+H]+: 131.

Into a 50-mL round-bottom flask, was placed2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (0.80 g, 4.23 mmol, 1.00equiv), THF (20 mL), TEA (0.51 g, 5.04 mmol, 1.19 equiv), and2-amino-N-tert-butylacetamide (0.58 g, 4.44 mmol, 1.05 equiv). Theresulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated. The residue was applied onto asilica gel column with ethyl acetate/hexane (0-50%). This resulted in0.688 g (57%) ofN-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino)acetamideas a white solid. LCMS (ES, m/z): [M+H]⁺: 283.1.

Example 1.8 Synthesis of1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane(Compound 92)

Scheme 6 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 100-mL round-bottom flask, was placed2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (500.00 mg, 2.645 mmol,1.00 equiv), acetonitrile (20.00 mL, 0.487 mmol, 0.18 equiv), azepane(314.78 mg, 3.174 mmol, 1.20 equiv), and TEA (321.17 mg, 3.174 mmol,1.20 equiv). The resulting solution was stirred for 2 hr at 80° C. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:3) togive 600 mg (90.10%) of1-[2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane as a solid.

Step 2

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed1-[2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane (300.00 mg,1.192 mmol, 1.00 equiv), dioxane (20.00 mL), 2-(tributylstannyl)pyridine(877.39 mg, 2.383 mmol, 2.0 equiv), and Pd(dppf)Cl₂ (43.60 mg, 0.060mmol, 0.05 equiv). The resulting solution was stirred overnight at 100degrees C. in an oil bath. The resulting mixture was concentrated. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:1). The crude product was purified byre-crystallization from EA (ethyl acetate). This resulted in 79 mg(24.16%) of1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane as awhite solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.66 (d, J=4.5 Hz, 1H), 8.25(d, J=7.8 Hz, 1H), 7.882 (t, J=7.8 Hz, 1H), 7.42 (dd, J=5.1 Hz, 6.0 Hz,1H), 3.78-3.64 (m, 4H), 3.11-3.00 (m, 2H), 2.83-2.78 (m, 2H), 2.08-1.97(m, 2H), 1.76 (s, 4H), 1.49 (s, 2H). LCMS: (ES) [M+1]⁺ m/z 295.2.

Example 1.9 Synthesis of4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-oxazepane(Compound 93)

Scheme 7 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 100-mL round-bottom flask, was placed2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (500.00 mg, 1.00 equiv),CH₃CN (10.00 mL), 1,4-oxazepane hydrochloride (402.00 mg, 1.10 equiv),and TEA (534.00 mg, 2.00 equiv). The resulting solution was stirred for3 hr at 80 degrees C. The reaction progress was monitored by LCMS. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:2). Thisresulted in 600 mg (89.28%) of4-[2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-oxazepane as abrown solid.

Step 2

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed4-[2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-oxazepane (0.30 g,1.18 mmol, 1.00 equiv), dioxane (20 mL), 2-(tributylstannyl)pyridine(0.87 g, 2.36 mmol, 2.0 equiv), Pd(dppf)Cl₂ (0.04 g, 0.035 mmol, 0.05equiv). The resulting solution was stirred overnight at 100° C. in anoil bath. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:1). The crude product was purified byre-crystallization from EA. This resulted in 358.1 mg (90%) of4-[2-(pyridin-2-yl)-5H,6H,7H-1-λ-4-cyclopenta[d]pyrimidin-4-yl]-1,4-oxazepaneas a light brown solid. 1H NMR (300 MHz, DMSO-d6): δ 8.66 (dd, J=0.9,0.9 Hz, 1H), 8.25 (d, J=7.8 Hz, 1H), 7.91-7.86 (m, 1H), 7.45-7.41 (m,1H), 3.97-3.87 (m, 4H), 3.85-3.75 (m, 2H), 3.66-3.62 (m, 2H), 3.08 (t,J=7.5 Hz, 2H), 2.85-2.80 (m, 2H), 2.06-1.96 (m, 4H). LCMS (ES) [M+1]+m/z 297.2.

Example 1.10 Synthesis of1-[2-(3-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane(Compound 71)

Compound 71 was synthesized similar to compound 92 replacing2-(tributylstannyl)pyridine with 4-fluoro-2-(tributylstannyl)pyridine.¹H NMR (400 MHz, Methanol-d₄) δ 8.46 (d, J=4.8 Hz, 1H), 7.77-7.68 (m,1H), 7.54 (dt, J=8.5, 4.3 Hz, 1H), 3.82 (t, J=6.1 Hz, 4H), 3.19 (t,J=7.4 Hz, 2H), 2.89 (t, J=7.9 Hz, 2H), 2.11 (p, J=7.7 Hz, 2H), 1.80 (s,4H), 1.59 (p, J=2.8 Hz, 4H). LCMS (ES) [M+1]⁺ m/z 312.4.

Example 1.11 Synthesis of5-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-2-oxa-5-azabicyclo[2.2.1]heptane(Compound 72)

Compound 72 was synthesized similar to compound 92 replacing azepanewith 2-oxa-5-azabicyclo[2.2.1]heptane. LCMS (ES+): (M+H)⁺=295.0. ¹H NMR(400 MHz, Chloroform-d) δ 8.85 (d, J=4.8 Hz, 1H), 8.40 (d, J=7.9 Hz,1H), 7.89-7.79 (m, 1H), 7.39 (dd, J=7.5, 4.9 Hz, 1H), 5.33 (s, 1H), 4.71(s, 1H), 4.00-3.94 (m, 2H), 3.83-3.76 (m, 2H), 3.20-2.96 (m, 4H),2.19-1.94 (m, 4H).

Example 1.12 Synthesis ofN-methyl-2-(pyridin-2-yl)-N-[(pyridin-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(Compound 73)

Scheme 8 depicts a synthetic route for preparing an exemplary compound.

Step 1

2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (204.00 mg; 1.08mmol; 1.00 eq.) was dissolved in acetonitrile (4 ml).2-pyridinylmethanamine (0.15 mL; 1.40 mmol; 1.30 eq.) was added followedby N, N-diisopropylethylamine (0.28 mL; 1.62 mmol; 1.50 eq.) slowly. Thereaction was stirred at 25° C. for 18 h, then at 50° C. for 6 h. Thesolvent was evaporated, and the residue was purified by silica gelchromatography (methanol/dichloromethane gradient) to give2-chloro-N-(pyridin-2-ylmethyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(277 mg, 98%) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.58(d, J=5.2 Hz, 1H), 7.97-7.88 (m, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.45-7.38(m, 1H), 6.63 (s, 1H), 4.86 (d, J=5.3 Hz, 2H), 2.87 (t, J=7.8 Hz, 2H),2.79 (t, J=7.5 Hz, 2H), 2.19-2.09 (m, 2H).

Step 2

2-Chloro-N-(pyridin-2-ylmethyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(274.00 mg; 1.05 mmol; 1.00 eq.) was suspended in 1,4-dioxane (5 ml) andmixture was purged with argon. 2-(Tributylstannyl)pyridine (0.74 mL;2.10 mmol; 2.00 eq.) and then tetrakis(triphenylphosphane) palladium(121.44 mg; 0.11 mmol; 0.10 eq.) were added. The reaction vessel wassealed, and the contents stirred in a heat bath at 105° C. for 16 h.Solvent was evaporated and the residue was purified by silica gelchromatography (methanol/dichloromethane gradient) to give2-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(161 mg, 50%) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.87(d, J=5.0 Hz, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.49 (d, J=8.0 Hz, 1H),7.94-7.88 (m, 1H), 7.80-7.73 (m, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.45 (dd,J=7.4, 4.9 Hz, 1H), 7.30-7.26 (m, 1H), 7.13 (s, 1H), 5.07 (d, J=5.1 Hz,2H), 3.11 (t, J=7.8 Hz, 2H), 2.95 (t, J=7.5 Hz, 2H), 2.24-2.16 (m, 2H).MS (ES+): (M+H)⁺=304.0.

Step 3

2-(Pyridin-2-yl)-N-(pyridin-2-ylmethyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(0.16 g; 0.53 mmol; 1.00 eq.) was dissolved in DMF (10 ml) and cooled inan ice bath. Sodium hydride (42 mg; 1.05 mmol; 2.00 eq.) (60%) was addedin two portions and the reaction was stirred for 45 m. Iodomethane (66μL; 1.05 mmol; 2.00 eq.) was added slowly and the mixture was stirredfor 1.5 h more. Water (20 ml) and ethyl acetate (100 ml) were added, thephases were separated, and the aqueous phase was extracted with moreethyl acetate (3×75 ml) and 3:1 chloroform:isopropanol (50 ml). Thecombined organic phases were washed with some water (5 ml) and driedover sodium sulfate. After evaporation of solvent, the residue waspurified by reverse phase chromatography (Waters XSelect CSH C18 column,0-70% acetonitrile/0.1% aqueous formic acid gradient). The purifiedfractions were treated with 1 M HCl and freeze-dried to giveN-methyl-2-(pyridin-2-yl)-N-[(pyridin-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-aminehydrochloride (90 mg, 48%) as a white solid. ¹H NMR (400 MHz,Chloroform-d) δ 9.08 (d, J=5.3 Hz, 1H), 8.69 (d, J=5.5 Hz, 1H), 8.62 (d,J=8.0 Hz, 1H), 8.29-7.98 (m, 3H), 7.75-7.68 (m, 1H), 7.55-7.47 (m, 1H),5.68 (s, 2H), 3.67 (s, 3H), 3.52-3.37 (m, 2H), 3.26-3.14 (m, 2H),2.23-2.12 (m, 2H). MS (ES+): (M+H)⁺=317.9.

Example 1.13 Synthesis ofN-(4-methoxyphenyl)-2-{methyl[2-(pyridin-2-yl)pyrimidin-4-yl]amino}acetamide(Compound 75)

Scheme 9 depicts a synthetic route for preparing an exemplary compound.

2-{4-[(Carboxymethyl)(methyl)amino]-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl}pyridin-1-iumchloride (Intermediate I) (150.00 mg; 0.35 mmol; 1.00 eq.) was suspendedin N,N-dimethylformamide (3.5 ml). N,N-Diisopropylethylamine (0.15 mL;0.87 mmol; 2.50 eq.), 4-methoxyaniline (57.5 mg; 0.47 mmol; 1.35 eq.)and then1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 177.6 mg; 0.47 mmol; 1.35 eq.) wereadded. After 40 h, ethyl acetate (50 ml) and sodium bicarbonate solution(20 ml) were added, the phases were separated, and the aqueous phase wasextracted with ethyl acetate (50 ml). The combined organic phases werewashed with sodium chloride solution and dried over sodium sulfate.After evaporation of the solvents, the residue was purified by reversephase chromatography (Waters XSelect CSH C18 column, 0-70%acetonitrile/0.1% aqueous formic acid gradient) to giveN-(4-methoxyphenyl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(formate salt, 46 mg, 34%) as a solid. ¹H NMR (400 MHz, Chloroform-d) δ10.18 (s, 1H), 8.86 (d, J=5.0 Hz, 1H), 8.53 (d, J=8.0 Hz, 1H), 8.22 (s,1H), 8.04-7.93 (m, 1H), 7.56-7.46 (m, 3H), 6.76 (d, J=8.6 Hz, 2H), 4.56(s, 2H), 3.74 (s, 3H), 3.50 (s, 3H), 3.24 (t, J=7.4 Hz, 2H), 2.99 (t,J=7.9 Hz, 2H), 2.12 (p, J=7.7 Hz, 2H). MS (ES+): (M+H)⁺=390.1.

Example 1.14 Synthesis ofN-(3-fluorophenyl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 74)

Compound 74 was synthesized similar to Compound 75 replacing4-methoxyaniline with 3-fluoroaniline. LCMS (ES+): (M+H)⁺=379.0. ¹H NMR(400 MHz, Chloroform-d) δ 10.80 (s, 1H), 9.10-8.96 (m, 1H), 8.67 (d,J=7.9 Hz, 1H), 8.21-8.09 (m, 1H), 7.72-7.58 (m, 2H), 7.40 (d, J=8.2 Hz,1H), 7.21-7.11 (m, 1H), 6.75-6.65 (m, 1H), 4.71 (s, 2H), 3.55 (s, 3H),3.29 (t, J=7.4 Hz, 2H), 2.97 (t, J=7.9 Hz, 2H), 2.14 (p, J=7.7 Hz, 2H).

Example 1.15 Synthesis of1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,2,3,4-tetrahydroquinoline(Compound 76)

Scheme 10 depicts a synthetic route for preparing an exemplary compound.

Step 1

To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine(100.00 mg; 0.53 mmol; 1.00 eq.) in AcCN (2 mL) was added1,2,3,4-tetrahydroquinoline (73.98 mg; 0.56 mmol; 1.05 eq.) followed byHunig's base (0.19 mL; 1.06 mmol; 2.00 eq.). The mixture was heated at75° C. for 2 h, the mixture was cooled and concentrated, the residue wasdiluted with water, the resulting precipitate was collected byfiltration, and dried under vacuum to give1-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}-1,2,3,4-tetrahydroquinoline(25 mg). LCMS (ES⁺): (M+H)⁺=286.2, 288.2.

Step 2

To a solution of1-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}-1,2,3,4-tetrahydroquinoline(25.00 mg; 0.09 mmol; 1.00 eq.) in toluene (1.5 mL) was added2-(tributylstannyl)pyridine (48.31 mg; 0.13 mmol; 1.50 eq.) andtetrakis(triphenylphosphane) palladium (10.11 mg; 0.01 mmol; 0.10 eq.).The mixture was degassed and heated at 110° C. for 15 h. The mixture wascooled and concentrated, diluted with AcCN and water, and subjected topurification by preparative HPLC to give1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,2,3,4-tetrahydroquinoline(36 mg). ¹H NMR (400 MHz, Methanol-d₄) δ 8.73-8.67 (m, 1H), 8.42 (dt,J=8.0, 1.2 Hz, 1H), 7.96 (td, J=7.8, 1.8 Hz, 1H), 7.50 (ddd, J=7.5, 4.9,1.3 Hz, 1H), 7.17 (q, J=7.5 Hz, 2H), 7.03 (td, J=7.5, 1.3 Hz, 1H), 6.77(d, J=7.9 Hz, 1H), 4.10 (t, J=6.5 Hz, 2H), 2.97 (t, J=7.7 Hz, 2H), 2.82(t, J=6.6 Hz, 2H), 2.31 (t, J=7.3 Hz, 2H), 2.02 (dp, J=36.1, 7.5, 7.0Hz, 4H). LCMS (ES+): (M+H)⁺=329.1.

Example 1.16 Synthesis of2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-phenylacetamide(Compound 77)

Compound 77 was synthesized similar to Compound 75 replacing4-methoxyaniline with aniline. LC MS (ES+): (M+H)⁺=360.0. ¹H NMR (400MHz, Chloroform-d) δ 10.39 (s, 1H), 8.98-8.87 (m, 1H), 8.58 (d, J=8.0Hz, 1H), 8.08-7.96 (m, 1H), 7.62 (d, J=8.0 Hz, 2H), 7.59-7.51 (m, 1H),7.25-7.17 (m, 2H), 7.01 (t, J=7.4 Hz, 1H), 4.61 (s, 2H), 3.52 (s, 3H),3.26 (t, J=7.4 Hz, 2H), 2.98 (t, J=7.9 Hz, 2H), 2.18-2.07 (m, 2H).

Example 1.17 Synthesis ofN-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 78)

Compound 78 was synthesized similar to Compound 75 replacing4-methoxyaniline with cyclohexanamine. ¹H NMR (400 MHz, Chloroform-d) δ9.07-8.93 (m, 1H), 8.59 (d, J=8.0 Hz, 1H), 8.12-8.01 (m, 1H), 7.83-7.64(m, 1H), 7.59 (d, J=6.7 Hz, 1H), 4.47 (s, 2H), 3.78-3.68 (m, 1H), 3.47(s, 3H), 3.24 (t, J=7.4 Hz, 2H), 3.00 (t, J=7.9 Hz, 2H), 2.17-2.07 (m,2H), 1.75 (d, J=12.0 Hz, 2H), 1.65-1.58 (m, 2H), 1.56-1.49 (m, 1H),1.28-1.06 (m, 5H). LCMS (ES+): (M+H)⁺=366.0.

Example 1.18 Synthesis of2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(oxan-4-yl)acetamide(Compound 79)

Compound 79 was synthesized similar to Compound 75 by replacing4-methoxyaniline with 4-aminotetrahydropyran. LCMS (ES+): (M+H)⁺=368.1.¹H NMR (400 MHz, Chloroform-d) δ 9.32 (s, 1H), 8.87 (d, J=8.0 Hz, 1H),8.81-8.73 (m, 1H), 8.45-8.35 (m, 1H), 7.92-7.84 (m, 1H), 4.76 (s, 2H),3.93-3.84 (m, 3H), 3.58 (s, 3H), 3.40-3.30 (m, 4H), 2.96 (t, J=7.9 Hz,2H), 2.16-2.11 (m, 2H), 1.75-1.56 (m, 4H).

Example 1.19 Synthesis ofN-ethyl-2-(pyridin-2-yl)-N-[(pyrimidin-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(Compound 80)

Compound 80 was synthesized similar to Compound 73 by replacing2-pyridinylmethanamine with 2-pyrimidinylmethylamine and replacingiodomethane with ethyl iodide. LCMS (ES+): (M+H)⁺=333.0. ¹H NMR (400MHz, Chloroform-d) δ 8.96-8.82 (m, 3H), 8.52 (d, J=7.7 Hz, 1H),8.18-8.09 (m, 1H), 7.75-7.68 (m, 1H), 7.55 (s, 1H), 5.43 (s, 2H), 4.01(q, J=7.1 Hz, 2H), 3.32-3.13 (m, 4H), 2.28-2.17 (m, 2H), 1.37 (t, J=6.9Hz, 3H).

Example 1.20 Synthesis ofN-methyl-2-(pyridin-2-yl)-N-[(pyrimidin-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(Compound 81)

Compound 81 was synthesized similar to Compound 73 by replacing2-pyridinylmethanamine with 2-pyrimidinylmethylamine. LCMS (ES+):(M+H)⁺=319.1. ¹H NMR (400 MHz, Chloroform-d) δ 8.78-8.69 (m, 3H), 8.33(s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.79-7.72 (m, 1H), 7.38-7.31 (m, 1H),7.22-7.17 (m, 1H), 5.14 (s, 2H), 3.53 (s, 3H), 3.21 (t, J=7.4 Hz, 2H),3.15-3.10 (m, 2H), 2.13-2.07 (m, 2H).

Example 1.21 Synthesis ofN-[(1,3-benzoxazol-2-yl)methyl]-N-methyl-2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(Compound 82)

Compound 82 was synthesized similar to Compound 73 by replacing2-pyridinylmethanamine with 1,3-benzoxazol-2-ylmethanamine. LCMS (ES+):(M+H)⁺=358.0. ¹H NMR (400 MHz, Chloroform-d) δ 8.82 (d, J=5.4 Hz, 1H),8.34 (d, J=8.0 Hz, 1H), 8.14 (s, 1H), 7.86-7.77 (m, 1H), 7.74-7.67 (m,1H), 7.54-7.47 (m, 1H), 7.41-7.35 (m, 1H), 7.35-7.29 (m, 2H), 5.25 (s,2H), 3.54 (s, 3H), 3.29 (t, J=7.3 Hz, 2H), 3.18-3.11 (m, 2H), 2.16-2.12(m, 2H).

Example 1.22 Synthesis of3-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-3-benzazepine(Compound 83)

Compound 83 was synthesized similar to compound 92 by replacing azepanewith 2,3,4,5-tetrahydro-1H-benzo[d]azepine. LCMS (ES+): (M+H)⁺=343.0. ¹HNMR (400 MHz, Chloroform-d) δ 8.81 (d, J=4.8 Hz, 1H), 8.41 (d, J=7.9 Hz,1H), 7.89-7.80 (m, 1H), 7.39 (dd, J=7.5, 4.9 Hz, 1H), 7.15 (s, 4H), 6.10(s, 2H), 4.08-3.99 (m, 4H), 3.15-3.02 (m, 8H), 2.19-2.08 (m, 2H).

Example 1.23 Synthesis ofN-(2-methoxyethyl)-N-methyl-2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(Compound 84)

Compound 84 was synthesized similar to compound 92 by replacing azepanewith N-(2-methoxyethyl)-N-methylamine. LCMS (ES+): (M+H)⁺=285.0. ¹H NMR(400 MHz, Chloroform-d) δ 8.81 (dd, J=4.7, 2.0 Hz, 1H), 8.45 (d, J=1.5Hz, 1H), 8.34 (dd, J=8.2, 1.5 Hz, 1H), 7.89-7.80 (m, 1H), 7.50-7.27 (m,3H), 3.97-3.90 (m, 2H), 3.70-3.63 (m, 2H), 3.41 (s, 3H), 3.36 (s, 3H),3.23-3.14 (m, 4H), 2.16-2.07 (m, 2H).

Example 1.24 Synthesis of1-methyl-4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane(Compound 85)

Compound 85 was synthesized similar to compound 92 by replacing azepanewith 1-methyl-1,4-diazepane. LCMS (ES+): (M+H)⁺=310.1. ¹H NMR (400 MHz,Chloroform-d) δ 8.79 (d, J=4.8 Hz, 1H), 8.29-8.21 (m, 1H), 7.86-7.76 (m,1H), 7.40-7.34 (m, 1H), 4.36-4.22 (m, 2H), 3.98 (t, J=6.7 Hz, 2H),3.50-3.40 (m, 2H), 3.28-3.18 (m, 2H), 3.11 (t, J=7.3 Hz, 2H), 3.03 (t,J=7.8 Hz, 2H), 2.82 (s, 3H), 2.56 (s, 2H), 2.15-2.04 (m, 2H).

Example 1.25 Synthesis of2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-1-(morpholin-4-yl)ethan-1-one(Compound 86)

Compound 86 was synthesized similar to Compound 75 by replacing4-methoxyaniline with morpholine. LCMS (ES+): (M+H)⁺=354.0. ¹H NMR (400MHz, Chloroform-d) δ 8.96-8.86 (m, 1H), 8.50-8.37 (m, 1H), 8.21-8.15 (m,1H), 8.07-7.93 (m, 1H), 7.60-7.48 (m, 1H), 4.86-4.75 (m, 2H), 3.81-3.74(m, 2H), 3.71-3.66 (m, 4H), 3.62-3.58 (m, 2H), 3.41 (s, 3H), 3.29-3.25(m, 2H), 3.06-3.00 (m, 2H), 2.17-2.05 (m, 2H).

Example 1.26 Synthesis ofN-methyl-N-(2-phenoxyethyl)-2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(Compound 87)

Compound 87 was synthesized similar to compound 92 by replacing azepanewith N-methyl-N-(2-phenoxyethyl)amine. LCMS (ES+): (M+H)⁺=285.0. ¹H NMR(400 MHz, Chloroform-d) δ 9.09 (d, J=4.9 Hz, 1H), 8.57 (d, J=7.8 Hz,1H), 8.16-8.00 (m, 1H), 7.69-7.63 (m, 1H), 7.29-7.25 (m, 2H), 6.98-6.91(m, 1H), 6.86 (d, J=8.0 Hz, 2H), 4.36 (s, 4H), 3.61 (s, 3H), 3.45 (t,J=7.8 Hz, 2H), 3.29 (t, J=7.3 Hz, 2H), 2.24-2.13 (m, 2H).

Example 1.27 Synthesis of2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-1-(piperidin-1-yl)ethan-1-one(Compound 88)

Compound 88 was synthesized similar to Compound 75 replacing4-methoxyaniline with piperidine. LCMS (ES+): (M+H)⁺=352.1. ¹H NMR (400MHz, Chloroform-d) δ 9.03 (d, J=5.1 Hz, 1H), 8.69-8.55 (m, 1H),8.23-8.07 (m, 1H), 7.74-7.64 (m, 1H), 5.17-4.78 (m, 2H), 3.64-3.56 (m,2H), 3.52 (t, J=5.6 Hz, 2H), 3.44 (s, 3H), 3.33-3.20 (m, 4H), 2.20-2.10(m, 2H), 1.73-1.62 (m, 4H), 1.57-1.49 (m, 2H).

Example 1.28 Synthesis ofN-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 89)

Compound 89 was synthesized similar to Compound 75 by replacing4-methoxyaniline with tert-butylamine. ¹H NMR (400 MHz, Chloroform-d) δ9.33-9.18 (m, 1H), 8.87 (d, J=7.7 Hz, 1H), 8.43-8.33 (m, 1H), 8.28 (s,1H), 7.91-7.79 (m, 1H), 4.71 (s, 2H), 3.55 (s, 3H), 3.29 (t, J=7.3 Hz,2H), 3.00 (t, J=7.9 Hz, 2H), 2.17-2.07 (m, 2H), 1.27 (s, 9H). MS (ES+):(M+H)⁺=340.0.

Example 1.29 Synthesis ofN-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 91)

Step 1

2-{[(Tert-butoxy)carbonyl](methyl)amino}propanoic acid (500 mg; 2.5mmol; 1 eq.) was dissolved in DMF (6 ml). N, N-diisopropylethylamine(1.1 mL; 6.15 mmol; 2.5 eq.) and then1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 1262 mg; 3.3 mmol; 1.35 eq.) wereadded. Cyclohexanamine (0.38 mL; 3.3 mmol; 1.35 eq.) was added and thereaction mixture was stirred at 25° C. After 14 h, the reaction wasdiluted with ethyl acetate (50 ml), water (15 ml) and sodium bicarbonatesolution (30 ml). The phases were separated, and the aqueous phase wasextracted with ethyl acetate (50 ml). the combined organics were washedwith sodium chloride solution (50 ml) and dried over sodium sulfate.After evaporation, the residue was purified by silica gel chromatography(ethyl acetate/hexanes gradient) to give tert-butylN-[1-(cyclohexylcarbamoyl)ethyl]-N-methylcarbamate (0.48 g, 68%) aswhite crystals. LCMS (ES+): (M+H)⁺=285.0.

Step 2

Tert-butyl N-[1-(cyclohexylcarbamoyl)ethyl]-N-methylcarbamate (0.48 g;1.7 mmol; 1 eq.) was dissolved in dichloromethane (12 ml) and cooled inan ice bath. Trifluoroacetic acid (6 mL) was added slowly and thereaction was stirred at 20° C. After 1.6 h, the reaction was evaporatedto a residue and then co-evaporated from toluene (40 ml). The crudeproduct of N-cyclohexyl-2-(methylamino)propanamide; trifluoroacetic acidsalt was used directly in the next step.

Step 3

2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (150 mg; 0.79 mmol;1 eq.) was dissolved in acetonitrile (3 ml) containingN-cyclohexyl-2-(methylamino)propenamide trifluoroacetic acid salt (355mg; 1.19 mmol; 1.5 eq.). N,N-diisopropylethylamine (0.55 mL; 3.2 mmol; 4eq.) was added and the reaction was stirred at 50° C. for 14 h, then at60° C. for 6 h, and to 30° C. over 18 h. After evaporation, the residuewas purified by silica gel chromatography (ethyl acetate/hexanesgradient) to give2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-cyclohexylpropanamide(174 mg, 65%) as a film. LCMS (ES+): (M+H)⁺=337.2.

Step 4

2-({2-Chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-cyclohexylpropanamide(174 mg; 0.52 mmol; 1 eq.) was dissolved in 1,4-dioxane (4 ml). and thesolution was purged with Ar gas. 2-(Tributylstannyl)pyridine (0.39 mL;1.03 mmol; 2 eq.) was added followed by tetrakis(triphenylphosphane)palladium (60 mg; 0.05 mmol; 0.1 eq.) The reaction vessel was sealed andstirred in a heat bath at 110° C. for 15 h. After evaporation, theresidue was purified by reverse phase chromatography (Waters XSelect CSHC18 column, 0-70% acetonitrile/0.1% aqueous formic acid gradient) togiveN-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propenamide(86 mg, 43%) as an off-white solid. LCMS (ES+): (M+H)⁺=380.0. ¹H NMR(400 MHz, DMSO-d6) δ 8.69 (d, J=4.8 Hz, 1H), 8.34 (d, J=7.9 Hz, 1H),8.19 (d, J=8.3 Hz, 1H), 7.96-7.84 (m, 1H), 7.53-7.42 (m, 1H), 5.16 (q,J=7.0 Hz, 1H), 3.63-3.49 (m, 1H), 3.25-3.16 (m, 1H), 3.14-3.06 (m, 4H),2.93-2.76 (m, 2H), 1.74 (s, 1H), 1.65 (s, 1H), 1.59-1.44 (m, 3H), 1.33(d, J=7.0 Hz, 3H), 1.25-1.12 (m, 3H), 1.07-0.93 (m, 2H).

Example 1.30 Synthesis ofN-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 90)

Compound 90 was synthesized similar to Compound 91 by replacingcyclohexanamine with tert-butylamine. LCMS (ES+): (M+H)⁺=354.4. ¹H NMR(400 MHz, DMSO-d6) δ 8.80-8.74 (m, 1H), 8.50 (d, J=7.9 Hz, 1H),8.09-8.01 (m, 1H), 7.81 (s, 1H), 7.66-7.59 (m, 1H), 5.14 (q, J=7.0 Hz,1H), 3.26 (s, 3H), 3.24-3.10 (m, 2H), 3.05-2.88 (m, 2H), 2.15-1.97 (m,3H), 1.40 (d, J=7.1 Hz, 3H), 1.21 (s, 9H).

Example 1.31 Synthesis of10-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-10-azatricyclo[6.3.1.0{circumflexover ( )}{2,7}]dodeca-2,4,6-triene (Compound 1)

Compound 1 was synthesized similar to compound 92 by replacing azepanewith 10-azatricyclo[6.3.1.0²,7]dodeca-2(7),3,5-triene. LCMS (ES+):(M+H)⁺=355.0. ¹H NMR (400 MHz, Chloroform-d) δ 8.66 (s, 1H), 8.45-8.12(m, 1H), 7.71 (s, 1H), 7.26-6.87 (m, 5H), 4.46-4.19 (m, 2H), 3.52-3.10(m, 4H), 2.99-2.74 (m, 4H), 2.34 (s, 1H), 2.01-1.76 (m, 3H).

Example 1.32 Synthesis of7-methoxy-3-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-3-benzazepine(Compound 2)

Compound 2 was synthesized similar to compound 92 by replacing azepanewith 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine. LCMS (ES+):(M+H)⁺=373.1 ¹H NMR (400 MHz, Chloroform-d) δ 8.90-8.70 (m, 1H), 8.40(d, J=7.1 Hz, 2H), 7.90-7.76 (m, 1H), 7.43-7.31 (m, 1H), 7.07 (d, J=8.2Hz, 1H), 6.77-6.60 (m, 2H), 4.10-3.91 (m, 4H), 3.79 (s, 3H), 3.15-2.91(m, 8H), 2.19-2.07 (m, 2H).

Example 1.33 Synthesis of6-methoxy-3-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-3-benzazepine(Compound 3)

Compound 3 was synthesized similar to compound 92 by replacing azepanewith 6-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine. LCMS (ES+):(M+H)⁺=373.0. ¹H NMR (400 MHz, Chloroform-d) δ 8.81 (dd, J=4.8, 1.8 Hz,1H), 8.42 (d, J=7.9 Hz, 1H), 7.86-7.77 (m, 1H), 7.39-7.31 (m, 1H),7.14-7.07 (m, 1H), 6.79-6.74 (m, 2H), 4.00 (dt, J=25.4, 4.9 Hz, 4H),3.81 (s, 3H), 3.17-3.03 (m, 8H), 2.15-2.06 (m, 2H).

Example 1.34 Synthesis of1-(3-methoxyphenyl)-4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane(Compound 4)

Scheme 11 depicts a synthetic route for preparing an exemplary compound.

Step 1

Tert-butyl4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane-1-carboxylate(200 mg; 0.51 mmol; 1 eq.) was dissolved in dichloromethane (5 ml).Trifluoroacetic acid (2.5 mL) was added slowly and the reaction wasstirred at 25° C. After 1 h, the reaction was evaporated to dryness andthe residue was co-evaporated with toluene. LCMS (ES+): (M+H)⁺=296.

Step 2

1-[2-(Pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane(108 mg; 0.37 mmol; 1.15 eq.) and 1-iodo-3-methoxybenzene (75 mg; 0.32mmol; 1 eq.) were mixed with 1,4-dioxane (1 ml) and tert-butanol (0.5ml). The mixture was purged with Ar gas.2-[2-(Dicyclohexylphosphanyl)phenyl]-N,N-dimethylaniline (25 mg; 0.06mmol; 0.20 eq.), tris(dibenzylideneacetone)dipalladium(0) (15 mg; 0.02mmol; 0.05 eq.) and sodium tert-butoxide (46 mg; 0.48 mmol; 1.50 eq.)were added and the reaction vessel was sealed and stirred at 100° C.After 19 h, additional portions of reagents (iodide, ligand, palladiumcatalyst and base) were added to drive product formation. The reactionmixture was then filtered, concentrated and purified by reverse phasechromatography (Waters XSelect CSH C18 column, 0-50% acetonitrile/0.1%aqueous formic acid gradient) to give1-(3-methoxyphenyl)-4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane(19 mg, 15%) as a yellow solid.

MS (ES+): (M+H)⁺=402.1. ¹H NMR (400 MHz, Chloroform-d) δ 8.94-8.87 (m,1H), 8.34 (d, J=7.9 Hz, 1H), 8.02-7.92 (m, 1H), 7.62-7.53 (m, 1H),7.19-7.10 (m, 1H), 6.41 (d, J=8.3 Hz, 1H), 6.35-6.28 (m, 2H), 4.30-4.22(m, 2H), 3.92-3.86 (m, 2H), 3.81-3.76 (m, 5H), 3.64 (t, J=6.2 Hz, 2H),3.36 (t, J=8.0 Hz, 2H), 3.18 (t, J=7.4 Hz, 2H), 2.27-2.15 (m, 4H).

Example 1.35 Synthesis ofN-(pyridin-2-yl)-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 5)

Scheme 12 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 50-mL 3-necked round-bottom flask, was placed[(tert-butoxycarbonyl)amino]acetic acid (2.0 g, 11.42 mmol, 1.0 equiv),DMF (20.0 mL), 2-aminopyridine (1.29 g, 13.71 mmol, 1.2 equiv) and DIPEA(3.69 g, 28.54 mmol, 2.5 equiv). This was followed by the addition ofHATU (5.21 g, 13.70 mmol, 1.2 equiv) in several batches at 0° C. Thereaction solution was stirred for 2 h at room temperature. The reactionwas then quenched by the addition of 50 mL of H₂O, filtered and thecollected solid was dried under infrared lamp. 2.4 g (84% yield) oftert-butyl N-[[(pyridin-2-yl)carbamoyl]methyl]carbamate was obtained aswhite solid. LCMS (ES) [M+1]⁺ m/z: 252.

Step 2

Into a 50-mL round-bottom flask, was placed tert-butylN-[[(pyridin-2-yl)carbamoyl]methyl]carbamate (2.40 g, 9.55 mmol, 1.0equiv) and DCM (20.0 mL). To the above mixture was added HCl (g) (2 M inEA) (19.0 mL) at 0° C. The mixture was stirred for 2 h at roomtemperature. The mixture was concentrated to remove the solvent, 1.4 g(78% yield) of 2-amino-N-(pyridin-2-yl)acetamide hydrochloride wasobtained as white solid. LCMS (ES) [M−HCl+1]⁺ m/z: 152.

Step 3

Into a 100-mL round-bottom flask, was placed2-amino-N-(pyridin-2-yl)acetamide hydrochloride (1.40 g, 7.46 mmol, 1.0equiv), NMP (30.0 mL), 2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine(1.30 g, 6.88 mmol, 0.9 equiv), DIEA (2.70 g, 20.89 mmol, 2.80 equiv).The mixture was stirred for 12 h at 60° C. in an oil bath. After beingcooled to room temperature, the reaction was diluted with H₂O (50 mL)and extracted with 3×40 mL of ethyl acetate. The combined organic phasewas washed with 3×40 ml of brine, dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column with ethyl acetate/petroleumether (1:2). 320 mg (14% yield) of2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino)-N-(pyridin-2-yl)acetamidewas obtained as a white solid. LCMS (ES) [M+1]⁺ m/z: 304.

Step 4

Into a 50-mL round-bottom flask, was placed2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino)-N-(pyridin-2-yl)acetamide(320 mg, 1.05 mmol, 1.0 equiv), dioxane (20.0 mL),2-(tributylstannyl)pyridine (465 mg, 1.26 mmol, 1.2 equiv), andPd(dppf)Cl₂ (86 mg, 0.11 mmol, 0.1 equiv). The mixture was stirred for12 h at 110° C. in an oil bath under N₂ atmosphere. The reaction mixturewas cooled to room temperature and concentrated to remove the solvent.The residue was purified by silica gel column with ethylacetate/petroleum ether (3:1). The crude product was further purified byFlash-Prep-HPLC with the following conditions: Column: HPH C18, 50*3.0mm, 2.6 um, Mobile Phase A: Water/0.05% NH₃·H₂O, Mobile Phase B: CH₃CN,Flow rate: 1.2 mL/min, Gradient: 5% B to 100% B within 1.1 min, hold 0.7min. 78.9 mg (22% yield) ofN-(pyridin-2-yl)-2-[[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamidewas obtained as off-white solid. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 10.60(s, 1H), 8.61 (d, J=4.6 Hz, 1H), 8.33 (dd, J=4.9, 1.1 Hz, 1H) 8.23 (d,J=8.1 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.78-7.69 (m, 2H), 7.40-7.35 (m,2H), 7.09 (ddd, J=7.3, 4.8, 1.0 Hz, 1H), 4.31 (d, J=5.8 Hz, 2H), 2.86(t, J=7.7 Hz, 2H), 2.79 (t, J=7.4 Hz, 2H), 2.09 (p, J=7.5 Hz, 2H). LCMS:(ES, m/z): [M+H]⁺: 347.1.

Example 1.36 Synthesis ofN-(2-fluorophenyl)-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 6)

Scheme 13 depicts a synthetic route for preparing an exemplary compound.

Into a 50-mL round-bottom flask, was placed[[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]aceticacid (160 mg, 0.59 mmol, 1.0 equiv), DMF (3.0 mL), 2-fluoroaniline (98mg, 0.88 mmol, 1.5 equiv), DIEA (153 mg, 1.18 mmol, 2.0 equiv) and HATU(337 mg, 0.88 mmol, 1.5 equiv). The resulting solution was stirred for 2h at room temperature. The reaction solution was diluted with 5 mL ofCH₃CN and filtered. The filtrate was purified by Prep-HPLC with thefollowing conditions (SHIMADZU (HPLC-01)): Column, Welch Xtimate C18,21.2*250 mm, 5 um, mobile phase, Water (10 mmol/L NH₄HCO₃) andMeOH:CH₃CN=1:1 (25% Phase B up to 65% in 15 min), Detector, UV, 254 nm.This provided 117.3 mg ofN-(2-fluorophenyl)-2-[[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamideas light yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.03 (br, 1H),8.63-8.61 (m, 1H), 8.31-8.28 (m, 1H), 7.88-7.75 (m, 2H), 7.50-7.37 (m,2H), 7.29-7.18 (m, 1H), 7.18-7.08 (m, 2H), 4.28 (d, J=5.4 Hz, 2H), 2.86(t, J=7.8 Hz, 2H), 2.78 (t, J=7.4 Hz, 2H), 2.14-2.04 (m, 2H). LCMS(ES)[M+1]⁺ m/z: 364.1.

Example 1.37 Synthesis of2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(quinolin-7-yl)acetamide(Compound 7)

Scheme 14 depicts a synthetic route for preparing an exemplary compound.

Into a 50-mL round-bottom flask at 0° C. was placed[[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]aceticacid (160 mg, 0.59 mmol, 1.0 equiv), DMF (3.0 mL), quinolin-7-amine (128mg, 0.88 mmol, 1.5 equiv), DIEA (153 mg, 1.18 mmol, 2.0 equiv) and HATU(337 mg, 0.88 mmol, 1.5 equiv). After addition, the mixture was stirredfor 2 h at room temperature. The reaction solution was diluted with 5 mLof CH₃CN and filtered. The filtrate was purified by Prep-HPLC with thefollowing conditions: Column, Welch Xtimate C18, 21.2*250 mm, 5 um,mobile phase, Water (10 mmol/L NH₄HCO₃) and MeOH:CH₃CN=1:1 (25% Phase Bup to 70% in 15 min); Detector, UV 254 nm. This provided 118.0 mg (50%)of2-((2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)-N-(quinolin-7-yl)acetamidewas obtained as grey solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.64 (s, 1H),8.82 (dd, J=4.2, 1.8 Hz, 1H), 8.64-8.61 (m, 1H), 8.43 (d, J=1.8 Hz, 1H),8.29-8.25 (m, 2H), 7.92 (d, J=8.7 Hz, 1H), 7.81-7.69 (m, 2H), 7.54-7.50(m, 1H), 7.43-7.36 (m, 2H), 4.30 (d, J=5.7 Hz, 2H), 2.90-2.76 (m, 4H),2.15-2.05 (m, 2H). LCMS: (ES, m/z): [M+1]⁺ m/z: 397.1.

Example 1.38 Synthesis ofN-tert-butyl-2-{[2-(pyrimidin-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 8)

Scheme 15 depicts a synthetic route for preparing an exemplary compound.

Into a 10-mL sealed tube purged and maintained in an inert atmosphere ofnitrogen, was placedN-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino)acetamide(0.30 g, 1.06 mmol, 1.00 equiv), dioxane (10 mL),4-(tributylstannyl)pyrimidine (0.47 g, 1.27 mmol, 1.20 equiv), andPd(dppf)Cl₂·CH₂Cl₂ (0.17 g, 0.20 equiv). The resulting solution wasstirred overnight at 130° C. The resulting mixture was concentrated. Theresidue was applied onto a silica gel column with MeOH/EA (1:9). Thecrude product was purified by Prep-HPLC with the following conditions:Column, welch Xtimate C18, 21.2*250 mm, 5 um; mobile phase; phase Awater (10 mmol/L NH₄HCO₃), phase B CH₃CN/MeOH (1:1) (15% B up to 60% in15 min); Detector, 220 nm. This resulted in 57.7 mg (16.7%) ofN-tert-butyl-2-[[2-(pyrimidin-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamideas a white solid. ¹H-NMR: (300 MHz, DMSO-d6, ppm): δ 9.28 (s, 1H), 8.93(d, J=5.1 Hz), 8.32 (d, J=5.1 Hz, 1H), 7.67 (s, 1H), 7.29 (t, J=6.0 Hz,1H), 3.97 (d, J=5.7 Hz, 2H), 2.87 (q, J=7.8 Hz, 2H), 2.76 (q, J=7.2 Hz,2H), 2.13-2.06 (m, 2H), 1.24 (s, 9H). LCMS: (ES, m/z): [M+H]⁺: 327.2.

Example 1.39 Synthesis ofN-tert-butyl-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino}acetamide(Compound 9)

Scheme 16 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 40-mL vial purged and maintained with an inert atmosphere ofnitrogen was placed 2,4-dichloro-5H,6H,7H-cyclopenta[b]pyridine (500.00mg, 2.66 mmol, 1.00 equiv), 2-(tributylstannyl)pyridine (1272.53 mg,3.46 mmol, 1.30 equiv), dioxane (10.00 mL), and Pd(PPh3)4 (307.25 mg,0.26 mmol, 0.10 equiv). The resulting solution was stirred overnight at110° C. The reaction mixture was cooled to room temperature. Theresulting mixture was concentrated. The crude product (1 g) was purifiedby Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBDColumn, 19 cm, 150 mm, 5 um; mobile phase, Water (0.1% NH3·H2O) and CAN(50% Phase B up to 80% in 11 min); Detector, 254. This resulted in 350mg (57.06%) of 2-[4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]pyridineas white solid. LCMS (ES) [M+H]+ m/z: 231.

Step 2

Into a 40-mL vial purged and maintained with an inert atmosphere ofnitrogen was placed2-[4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]pyridine (160.00 mg, 0.69mmol, 1.00 equiv), 2-amino-N-tert-butylacetamide (99.32 mg, 0.76 mmol,1.10 equiv), Pd(OAc)2 (15.57 mg, 0.069 mmol, 0.10 equiv), Cs2CO3 (451.94mg, 1.38 mmol, 2.00 equiv), BINAP (86.37 mg, 0.14 mmol, 0.20 equiv),dioxane (10.00 mL). The resulting solution was stirred for overnight at100° C. The reaction mixture was cooled to room temperature. Theresulting mixture was concentrated. The crude product (300 mg) waspurified by Prep-HPLC with the following conditions: Column, XBridgePrep C18 OBD Column, 19 cm, 150 mm, 5 um; mobile phase, Water (0.1%NH4HCO3) and CAN (20% Phase B up to 50% in 11 min); Detector, 254 nm.This resulted in 167.7 mg (74.53%) ofN-tert-butyl-2-[[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino]acetamideas off-white solid. 1HNMR (300 MHz, DMSO-d6) δ 8.59 (ddd, J=4.8, 1.9,0.9 Hz, 1H), 8.30 (dt, J=8.0, 1.1 Hz, 1H), 7.84 (td, J=7.7, 1.8 Hz, 1H),7.66 (s, 1H), 7.41-7.30 (m, 2H), 6.00 (t, J=5.7 Hz, 1H), 3.77 (d, J=5.7Hz, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.75 (t, J=7.3 Hz, 2H), 2.12-2.02 (m,2H), 1.27 (s, 9H). LCMS (ES, m/z): [M+H]+: 325.1.

Example 1.40 Synthesis ofN-tert-butyl-2-{[2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4-yl]amino}acetamide(Compound 10)

Scheme 17 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 40-mL vial, was placed 2,4-dichloro-5,6,7,8-tetrahydroquinazoline(1.00 g, 4.92 mmol, 1.00 equiv), 2-amino-N-tert-butylacetamide (0.71 g,5.47 mmol, 1.11 equiv), DIEA (1.27 g, 9.85 mmol, 2.00 equiv), and CH₃CN(10.00 mL). The resulting solution was stirred overnight at 80° C. Thereaction mixture was cooled to room temperature. The crude product (2 g)was purified by Prep-HPLC with the following conditions: Column, XBridgePrep C18 OBD Column, 19 cm, 150 mm, 5 um; mobile phase, Water (0.1%NH3·H2O) and CAN (20% Phase B up to 60% in 11 min); Detector, 254. Thisresulted in 1.1 g (75.26%) ofN-tert-butyl-2-[(2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)amino]acetamideas a white solid. LCMS (ES) [M+H]+ m/z: 297.

Step 2

Into a 40-mL vial purged and maintained with an inert atmosphere ofnitrogen, was placedN-tert-butyl-2-[(2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)amino]acetamide(500.00 mg, 1.68 mmol, 1.00 equiv), 2-(tributylstannyl)pyridine (806.26mg, 2.19 mmol, 1.30 equiv), dioxane (10.00 mL) and Pd(dppf)Cl₂ (123.26mg, 0.17 mmol, 0.10 equiv). The resulting solution was stirred forovernight at 110° C. The reaction mixture was cooled to roomtemperature. The resulting mixture was concentrated. The crude product(800 mg) was purified by Prep-HPLC with the following conditions:Column, XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um; mobile phase,Water (0.1% NH₄HCO₃) and CAN (20% Phase B up to 50% in 11 min);Detector, 254 nm. This resulted in 139.2 mg (24.34%) ofN-tert-butyl-2-[[2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4-yl]amino]acetamideas white solid. ¹H-NMR (300 MHz, DMSO-d6) δ8.65 (ddd, J=4.8, 1.8, 0.9Hz, 1H), 8.33 (dt, J=8.0, 1.1 Hz, 1H), 7.87 (td, J=7.7, 1.8 Hz, 1H),7.71 (s, 1H), 7.45-7.40 (m, 1H), 6.88 (t, J=5.6 Hz, 1H), 3.95 (d, J=5.6Hz, 2H), 2.73-2.63 (m, 2H), 2.46-2.38 (m, 2H), 1.81-1.78 (m, 4H), 1.24(s, 9H). LCMS (ES, m/z): [M+H]⁺: 340.1

Example 1.41 Synthesis ofN-(4-methoxyphenyl)-1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]piperidin-3-amine(Compound 11)

Step 1

1-Bromo-4-methoxybenzene (0.25 g; 1.34 mmol; 1 eq.) and tert-butyl3-amino-1-piperidinecarboxylate (0.32 g; 1.6 mmol; 1.2 eq.) weredissolved in 1,4-dioxane (5 ml) and tert-butanol (2.5 ml). The solutionwas purged with Ar gas, and sodium tert-butoxide (0.26 g; 2.67 mmol; 2eq.), 2-[2-(dicyclohexylphosphanyl)phenyl]-N,N-dimethylaniline (52.6 mg;0.13 mmol; 0.1 eq.) and tris(dibenzylideneacetone)dipalladium(0) (61.2mg; 0.07 mmol; 0.05 eq.) were added. The sealed reaction vessel wasstirred in a heat bath at 100° C. for 6 h. After cooling andevaporation, the residue was purified by silica gel chromatography(ethyl acetate/hexanes gradient) to give tert-butyl3-[(4-methoxyphenyl)amino]piperidine-1-carboxylate (178 mg, 43%) as asolid. LCMS (ES+): (M+H)⁺=307.0. ¹H NMR (400 MHz, Chloroform-d) δ6.82-6.76 (m, 2H), 6.76-6.60 (m, 2H), 4.09-3.93 (m, 1H), 3.76-3.67 (m,4H), 3.33-3.22 (m, 1H), 3.09-2.95 (m, 1H), 2.95-2.75 (m, 1H), 2.07-1.95(m, 1H), 1.76-1.68 (m, 1H), 1.45 (s, 9H).

Step 2

Tert-butyl 3-[(4-methoxyphenyl)amino]piperidine-1-carboxylate (178 mg;0.58 mmol; 1 eq.) was dissolved in DCM (5 ml) and cooled in an ice bath.Trifluoroacetic acid (2.55 mL) was added slowly and the reaction wasstirred at 20° C. for 1 h. The reaction was evaporated, and the residuewas co-evaporated with toluene to give3-[(4-methoxyphenyl)amino]piperidin-1-ium trifluoroacetate, which wasused directly in the next step.

Step 3

In a round bottom flask was added2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (100.00 mg; 0.53mmol; 1.00 eq.), acetonitrile (3.5 ml),3-[(4-methoxyphenyl)amino]piperidin-1-ium trifluoroacetate (186.38 mg;0.58 mmol; 1.10 eq.) Hunig's base (0.38 mL; 2.17 mmol; 4.10 eq.). Themixture was stirred at ˜70° C. After cooling and evaporation, theresidue was purified by silica gel chromatography (0 to 50% ethylacetate/hexanes gradient) to give1-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}-N-(4-methoxyphenyl)piperidin-3-amine(144 mg, 76%). LCMS (ES+): (M+H)⁺=402.4.

Step 4

In a round bottom flask was added1-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}-N-(4-methoxyphenyl)piperidin-3-amine(144.00 mg; 0.40 mmol; 1.00 eq.) in 1,4-dioxane (dry, ˜3 ml). Thesolution was purged with Ar. To the mixture was added2-(tributylstannyl)pyridine (0.26 mL; 0.80 mmol; 2.00 eq.) andtetrakis(triphenylphosphane) palladium (46.37 mg; 0.04 mmol; 0.10 eq.)After being stirred in a heat block at 105° C. for 15 h, the mixture wasconcentrated and the residue was purified by preparative HPLC to giveN-(4-methoxyphenyl)-1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]piperidin-3-amine(52 mg) as a yellow solid. LCMS (ES+): (M+H)⁺=402.4. ¹H NMR (400 MHz,Chloroform-d) δ 9.01-8.83 (m, 1H), 8.38 (d, J=8.6 Hz, 1H), 8.00-7.86 (m,1H), 7.55-7.43 (m, 1H), 7.08-6.87 (m, 2H), 6.87-6.69 (m, 2H), 4.79 (s,1H), 4.16-4.00 (m, 1H), 3.74 (s, 3H), 3.62-3.44 (m, 3H), 3.17-2.87 (m,4H), 2.17-1.99 (m, 3H), 1.99-1.75 (m, 2H), 1.70-1.52 (m, 1H).

Example 1.42 Synthesis ofN-tert-butyl-2-{[2-(5-methoxypyrazin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 12)

Scheme 18 depicts a synthetic route for preparing an exemplary compound.

Into a 40-mL vial purged and maintained in an inert atmosphere ofnitrogen was placed a mixture ofN-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(200 mg, 0.674 mmol, 1.00 equiv), dioxane (10.0 ml),2-methoxy-5-(trimethylstannyl)pyrazine (275 mg, 1.01 mmol, 1.50 equiv),and Pd(PPh₃)₄ (155 mg, 0.135 mmol, 0.20 equiv). The resulting solutionwas stirred for 16 hours at 110° C. The resulting mixture wasconcentrated. The crude reaction mixture was filtered and subjected toreverse phase preparative MPLC (Prep-C18, 20-45 mM, 120 g, TianjinBonna-Agela Technologies; gradient elution of 5% MeCN in water to 35%MeCN in water over a 15 min period, where both solvents contain 0.1%formic acid). This resulted in 71.7 mg (28%) ofN-(tert-butyl)-2-((2-(5-methoxypyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas an off-white solid. ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 9.12 (d, J=1.4Hz, 1H), 8.36 (d, J=1.3 Hz, 1H), 7.68 (s, 1H), 4.13 (s, 2H), 3.98 (s,3H), 3.27 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H),2.00-1.95 (m, 2H), 1.25-1.22 (m, 9H). LCMS (ES) [M+1]⁺ m/z: 371.2.

Example 1.43A Synthesis ofN-tert-butyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 174)

Scheme 19A depicts a synthetic route for preparing an exemplarycompound.

Step 1

Into a 250-mL 3-necked round-bottom flask was placed ethyl2-hydroxy-2-methylpropanoate (10.0 g, 75.8 mmol, 1.00 equiv),3,4-dihydro-2H-pyran (9.54 g, 113.7 mmol, 1.50 equiv) in dichloromethane(100 mL), and pyridine 4-methylbenzenesulfonate (0.95 g, 3.79 mmol, 0.05equiv). The resulting solution was stirred for 3 h at room temperature.The reaction mixture was poured into water and extracted with Et₂O. Theorganic layers were dried over Na₂SO₄, filtered, and the filtrate wasconcentrated in vacuo. The crude residue was purified by silica gelchromatography (hexane/ethyl acetate, 100:0 to 5:1) to give 15.6 g (95%)of ethyl 2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate as acolorless oil.

Step 2

Into a 500-mL 3-round-bottom flask was placed ethyl2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate (15.0 g, 69.4 mmol,1.00 equiv) in THE (150.00 mL). Lithium aluminium hydride (69.4 mL, 1mol/L, 69.4 mmol, 1.00 equiv) was added portion-wise at 0° C. Thereaction mixture was stirred for 5 h, followed by the slow addition ofNa₂SO₄.10H₂O (22.3 g, 69.4 mmol, 1.00 equiv). After 30 minutes ofstirring at 0° C., the mixture was filtered and the filtrate wasconcentrated in vacuo to give2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (8.9 g, 74%) as acolorless oil which was used in the next step without furtherpurification.

Step 3

Into a 250 mL 3-neck flask was placed2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (3.9 g, 22.4 mmol,2.0 equiv) and DMF (50 mL), NaH (60% in mineral oil) (896 mg, 22.4 mmol,2.0 equiv) was added portion-wise at 0-5° C. The mixture was stirred for1 h at room temperature. After that,N-(tert-butyl)-2-((2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(4 g, 11.2 mmol, 1.00 equiv) was added at 0-5° C. The reaction mixturewas stirred for 5 h at 50° C. (The reaction was repeated in 2 batches).The reaction mixture was cooled to room temperature, diluted with 150 mLof water, and extracted with 3×100 mL of ethyl acetate. The combinedorganic phase was washed with 3×150 mL of water and brine 1×100 mL,dried over anhydrous sodium sulfate, and concentrated to afford 10 gcrude product (87% yield). This was directly used in the next stepwithout purification. LCMS (ES) [M+1]⁺ m/z: 512.

Step 4

Into a 250 mL 3-neck flask was placedN-(tert-butyl)-2-(methyl(2-(4-(2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide(crude product from step 3, 10 g, 19.5 mmol, 1.00 equiv) and MeOH (50mL). HCl (20 mL, 1N) was added in portion wise at 0-5° C. The mixturewas stirred for 3 h at room temperature. The reaction mixture wasconcentrated, and the residue was purified by Prep-HPLC with thefollowing conditions: column, C18-800 g, Mobile phase, CH₃CN/H₂O (0.05%FA), from 10% increased to 70% within 27 min, Flow rate, 180 mL/min,Detector, 254 nm. The pH value of the fraction was adjusted to 7˜8 withK₂CO₃ solid, and extracted with dichloromethane (3×300 mL). The combinedorganic phase was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The residue wasfreezing dried, and this resulted in 5.3 g (64%) ofN-(tert-butyl)-2-((2-(4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a white solid. LCMS: (ES, m/z): [M+H]⁺: 428.3. ¹H NMR (300 MHz,DMSO-d₆): δ 8.47 (d, J=5.6 Hz, 1H), 7.82 (d, J=2.5 Hz, 1H), 7.67 (s,1H), 7.04 (dd, J=5.7, 2.6 Hz, 1H), 4.69 (s, 1H), 4.14 (s, 2H), 3.86 (s,2H), 3.26 (s, 3H), 3.15 (t, J=7.4 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H),2.04-1.94 (m, 2H), 1.25-1.24 (m, 15H).

Example 1.43B (Alternative Method for Preparing Compound 174)

Into a 250 mL three-necked round bottom flask were addedN-(tert-butyl)-2-((2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(7.2 g, 19.3 mmol, 1.00 equiv) and DMSO (80 mL). This was followed bythe addition of NaH (60% in mineral oil) (1.5 g, 38.6 mmol, 2.00 equiv)at room temperature. The mixture was stirred for 0.5 h, and2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (6.7 g, 38.6 mmol,2.00 equiv) was added to the above mixture and stirred for an additional3 h at 40° C. The reaction mixture was cooled to room temperature,quenched with H₂O (100 mL), and extracted with ethyl acetate (100 mL*2).The combined organic phases were washed with brine (100 mL*2), driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified byPrep-HPLC with the following conditions: C18-500 g, CH₃CN/H₂O (NH₄HCO₃0.1%), from 15% to 70% in 30 min, Flow rate, 150 mL/min, Detector, UV254 nm. This resulted in 7.0 g (71%)N-(tert-butyl)-2-(methyl(2-(4-(2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamideas a brown solid. LCMS (ES, m/z): [M+H]⁺: 512.

Into a 250 mL three-necked round bottom flask were addedN-(tert-butyl)-2-(methyl(2-(4-(2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide(7.0 g, 13.7 mmol, 1.00 equiv) and methanol (70 mL), HCl (c) (5 mL). Themixture was stirred for 0.5 h, diluted with H₂O (200 mL), and the pHvalue was adjusted to 9 with K₂CO₃ solid. The mixture was extracted withdichloromethane (300 mL*2), the combined organic phase was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The residue 5.8 g (purity: 96.7%) was trituratedin CH₃CN (120 mL), filtered, and 5.5 g (98.8% purity) was obtained. Thecrude product was dissolved in CH₃CN (110 mL) at 60° and then cooled to20° C. in 20 min. The solid was collected by filtration and dried underan infrared lamp for 1 h. This resulted in 3.1 g (99.94% purity, 56.3%yield)N-(tert-butyl)-2-((2-(4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a white solid. LCMS: (ES, m/z): [M+H]⁺: 428. ¹H-NMR (300 MHz,DMSO-d₆, ppm): δ 8.48 (d, J=5.4 Hz, 1H), 7.83 (d, J=2.7 Hz, 1H), 7.67(s, 1H), 7.05 (dd, J=5.7, 2.7 Hz, 1H), 4.69 (s, 1H), 4.14 (s, 2H), 3.86(s, 2H), 3.26 (s, 3H), 3.15 (t, J=7.2 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H),2.04-1.94 (m, 2H), 1.25 (s, 9H), 1.24 (s, 6H).

Example 1.44 Synthesis of2-[4-(azepan-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]-N,N-dimethylpyridin-4-amine(Compound 13)

Compound 13 was synthesized similar to Compound 92, by replacing(2-tributylstannyl)pyridine withN,N-dimethyl-2-(tributylstannyl)pyridin-4-amine. ¹H NMR (400 MHz,DMSO-d₆) δ 8.19 (d, J=7.2 Hz, 1H), 7.75 (d, J=3.1 Hz, 1H), 7.05 (dd,J=7.3, 2.9 Hz, 1H), 3.86 (d, J=3.4 Hz, 1H), 3.86-3.72 (m, 3H), 3.26 (s,6H), 3.12 (hept, J=7.3, 6.7 Hz, 2H), 3.00-2.80 (m, J=8.0 Hz, 2H), 2.04(h, J=8.2, 7.8 Hz, 2H), 1.73 (dq, J=18.9, 7.4, 6.4 Hz, 4H), 1.48 (dq,J=7.4, 4.6, 3.7 Hz, 4H). LCMS (ES+): (M+H)⁺=338.1.

Example 1.45 Synthesis of1-[2-(4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane(Compound 14)

Compound 14 was synthesized similar to Compound 92 replacing(2-tributylstannyl)pyridine with 4-methyl-2-(tributylstannyl)pyridine.¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (d, J=5.0 Hz, 1H), 8.27 (d, J=1.7 Hz,1H), 7.64-7.58 (m, 1H), 3.97 (s, 4H), 3.22-3.10 (m, 2H), 3.03 (t, J=7.9Hz, 2H), 2.51 (s, 3H), 2.09 (p, J=7.7 Hz, 2H), 1.82 (s, 4H), 1.54 (s,4H). LCMS (ES+): (M+H)⁺=309.2.

Example 1.46 Synthesis ofN-(2-methoxyphenyl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 15)

Scheme 20 depicts a synthetic route for preparing an exemplary compound.

To a solution of2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}aceticacid (65.00 mg; 0.23 mmol; 1.00 eq.) in DMF (1.5 mL) was added2-methoxyaniline (33.79 mg; 0.27 mmol; 1.20 eq.) followed by Hunig'sbase (0.08 mL; 0.46 mmol; 2.00 eq.), and HATU (86.93 mg; 0.23 mmol; 1.00eq.). After being stirred for 1 h at room temperature, it was dilutedwith water and acetonitrile and the mixture was subjected topurification by preparative HPLC to giveN-(2-methoxyphenyl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(9 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 9.39 (s, 1H), 8.66-8.59 (m, 1H),8.31-8.24 (m, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.78 (td, J=7.7, 1.8 Hz, 1H),7.40 (ddd, J=7.5, 4.7, 1.2 Hz, 1H), 7.07-6.95 (m, 2H), 6.85 (td, J=7.5,7.0, 1.7 Hz, 1H), 4.49 (s, 2H), 3.68 (s, 3H), 3.31 (s, 3H), 3.18 (t,J=7.3 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.00 (dq, J=15.2, 8.3, 7.8 Hz,2H). LCMS (ES+): (M+H)⁺=390.3.

Example 1.47 Synthesis ofN-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino}acetamide(Compound 16)

Scheme 21 depicts a synthetic route for preparing an exemplary compound.

Into a 40-mL vial purged and maintained in an inert atmosphere ofnitrogen, was placed2-[4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]pyridine (100.00 mg, 0.43mmol, 1.00 equiv), N-tert-butyl-2-(methylamino)acetamide (81.27 mg, 0.56mmol, 1.30 equiv), Pd(OAc)₂ (9.73 mg, 0.04 mmol, 0.10 equiv), BINAP(53.98 mg, 0.08 mmol, 0.20 equiv), Cs₂CO₃ (282.46 mg, 0.86 mmol, 2.00equiv) and dioxane (6.00 mL). The resulting solution was stirredovernight at 100° C. The reaction mixture was cooled to roomtemperature. The resulting mixture was concentrated. The crude product(200 mg) was purified by Prep-HPLC with the following conditions:Column, XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um; mobile phase,Water (0.1% NH₄HCO₃) and AcCN (30% Phase B up to 60% in 11 min);Detector, 254 nm. This resulted in 71.5 mg (48.74%) ofN-tert-butyl-2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino]acetamideas off-white solid. ¹H-NMR (300 MHz, DMSO-d6) δ 8.62 (dd, J=4.8, 1.7 Hz,2H), 8.31 (dt, J=8.0, 1.2 Hz, 1H), 7.86 (td, J=7.7, 1.9 Hz, 1H), 7.57(s, 1H), 7.55 (s, 1H), 7.37 (ddd, J=7.5, 4.7, 1.2 Hz, 1H), 3.94 (s, 2H),3.07 (s, 3H), 3.03 (t, J=7.2 Hz, 2H), 2.86 (t, J=7.7 Hz, 2H), 2.05-1.95(m, 2H), 1.28 (s, 9H). LCMS (ES, m/z): [M+H]⁺: 339.2.

Example 1.48 Synthesis ofN-tert-butyl-2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide(Compound 245)

Scheme 22 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 500-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed oxetan-3-ol (8.45 g, 114.04mmol, 1.50 equiv) and THF (100.00 mL). This was followed by the additionof NaH (60% in mineral oil) (6.84 g, 171.06 mmol, 1.50 equiv) in severalbatches at 0° C. The mixture was stirred at 0° C. for 30 min.2-chloro-4-fluoropyridine (10.00 g, 76.02 mmol, 1.00 equiv) was addeddropwise with stirring at 0° C. After addition, the resulting solutionwas stirred for 6 h at room temperature. The reaction mixture was cooledto 0° C. again, quenched carefully by the addition of 30 mL of water,extracted with 3×100 mL of ethyl acetate. The combined organic phase wasdried over anhydrous sodium sulfate, filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column with ethyl acetate/petroleum ether (1:2). This resulted in 11g (78%) of 2-chloro-4-(oxetan-3-yloxy)pyridine as a white solid. LCMS(ES) [M+1]⁺ m/z: 186.

Step 2

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed2-chloro-4-(oxetan-3-yloxy)pyridine (2.00 g, 10.81 mmol, 1.00 equiv),toluene (60.00 mL), Sn₂Me₆ (3.71 g, 11.31 mmol, 1.05 equiv), Pd(PPh₃)₄(1.25 g, 1.08 mmol, 0.10 equiv). The mixture was stirred for 4 h at 100°C. in oil bath. The reaction mixture was cooled to room temperature andused to the next step without purification. This reaction was repeatedthree times. LCMS (ES) [M+1]⁺ m/z: 316.

Step 3

Into the reaction solution of step 3 purged and maintained with an inertatmosphere of nitrogen,N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(2.23 g, 7.54 mmol, 0.70 equiv) and Pd(PPh₃)₄ (1.24 g, 1.07 mmol, 0.10equiv) were added. The resulting solution was stirred for 12 h at 100°C. in oil bath. This parallel reaction was repeated three times. Thereaction mixture was cooled and concentrated to remove the solvent. Theresidue was purified by silica gel column with ethyl acetate/petroleumether (from 10% to 100%). This resulted in 7.2 g crude compound, whichwas further purified by Prep-HPLC with conditions: column, C18-800 g,Mobile phase, CH₃CN/H₂O (0.05% FA), from 10% increased to 70% within 27min, Flow rate, 180 mL/min, Detector, 254 nm. The pH value of thefraction was adjusted to 7˜8 with K₂CO₃ solid, extracted withdichloromethane (3×300 mL). The combined organic phase was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure. The residue was triturated indichloromethane/hexane (1:10, 30 mL), filtered and the solid wasfreezing dried to give 5.2 g (56%) ofN-tert-butyl-2-[methyl([2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl])amino]acetamideas a white solid. LCMS: (ES, m/z): [M+H]⁺: 412. ¹H-NMR: (300 MHz,DMSO-d₆, ppm): δ 8.49 (d, J=5.4 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.70(s, 1H), 6.87 (dd, J=5.7, 2.4 Hz, 1H), 5.52-5.45 (m, 1H), 4.99 (t, J=6.6Hz, 2H), 4.58 (dd, J=7.2, 4.8 Hz, 2H), 4.13 (s, 2H), 3.29 (s, 3H), 3.15(t, J=7.2 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.05-1.94 (m, 2H), 1.26 (s,9H).

Example 1.49 Synthesis ofN-cyclohexyl-1-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}cyclopropane-1-carboxamide(Compound 17)

Scheme 23 depicts a synthetic route for preparing an exemplary compound.

Step 1

To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine(500.00 mg; 2.64 mmol; 1.00 eq.) in AcCN (5 mL) was added DIPEA (1.15mL; 6.61 mmol; 2.50 eq.) and ethyl 1-aminocyclopropane-1-carboxylate(409.93 mg; 3.17 mmol; 1.20 eq.). The mixture was heated at 60° C. for24 h, and 80° C. for an additional 4 days (HPLC showed the conversion tobe about 50%). The reaction was stopped and the mixture wasconcentrated, the resulting crude residue was purified by columnchromatography (hexanes/EtOAc=1:1) to give ethyl1-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}amino)cyclopropane-1-carboxylate(135 mg). LCMS (ES⁺): (M+H)⁺=282.0, 284.1.

Step 2

To a solution of ethyl1-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}amino)cyclopropane-1-carboxylate(135.00 mg; 0.48 mmol; 1.00 eq.) in DMF (2 mL) was added sodium hydride(57.49 mg; 1.44 mmol; 3.00 eq.) at 0° C. After being stirred for 10 min,to the mixture was added iodomethane (0.04 mL; 0.72 mmol; 1.50 eq.) andthe solution was further stirred at ambient temperature until finished.The mixture was diluted with Sat. NaHCO₃ and EtOAc, the organic layerwas separated, and the aqueous layer was further extracted with EtOAc(2×). The combined organic layer was washed with brine, dried, andconcentrated to give ethyl1-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)cyclopropane-1-carboxylate(66 mg), which was used for the next step without further purification.LCMS (ES⁺): (M+H)⁺=296.1, 298.4.

Step 3

To a solution of ethyl1-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)cyclopropane-1-carboxylate(66.00 mg; 0.22 mmol; 1.00 eq.) in THF (1 mL) was added MeOH (0.5 mL)and water (0.5 mL) followed by lithium hydroxide monohydrate (18.73 mg;0.45 mmol; 2.00 eq.). The mixture was stirred for 2 h at roomtemperature and was heated to 60° C. and stirred for an additional 2 h.The mixture was cooled and concentrated under vacuum, the residue wasacidified with 1N HCl to pH=3, and the aqueous layer was freeze-dried togive1-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)cyclopropane-1-carboxylicacid, which was used for the next step without purification. LCMS (ES⁺):(M+H)⁺=268.1, 270.2.

Step 4

To a solution of1-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)cyclopropane-1-carboxylicacid (100.00 mg; 0.37 mmol; 1.00 eq.) and cyclohexanamine (0.05 mL; 0.45mmol; 1.20 eq.) in DMF (1 mL) was added DIPEA (0.13 mL; 0.75 mmol; 2.00eq.) and HATU (142.03 mg; 0.37 mmol; 1.00 eq.). After being stirred atroom temperature for 1 h, the mixture was diluted with water and theprecipitate was collected by filtration, and dried under vacuum to give1-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-cyclohexylcyclopropane-1-carboxamide(73 mg). LCMS (ES⁺): (M+H)⁺=268.1, 270.2.

Step 5

To a solution of1-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-cyclohexylcyclopropane-1-carboxamide(70.00 mg; 0.20 mmol; 1.00 eq.) and 2-(tributylstannyl)pyridine (110.80mg; 0.30 mmol; 1.50 eq.) in Toluene (1 mL) was addedtetrakis(triphenylphosphane) palladium (23.19 mg; 0.02 mmol; 0.10 eq.).The solution was degassed with N₂ and heated at 105° C. for 15 h. Themixture was cooled and concentrated, and the residue was subjected topurification by preparative HPLC to giveN-cyclohexyl-1-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}cyclopropane-1-carboxamide(23 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 8.69-8.62 (m, 1H), 8.27 (d, J=7.9Hz, 1H), 7.88 (td, J=7.7, 1.8 Hz, 2H), 7.58 (ddd, J=18.1, 10.7, 6.9 Hz,1H), 7.42 (ddd, J=7.5, 4.7, 1.2 Hz, 1H), 3.62 (s, 1H), 3.13 (s, 3H),2.93-2.81 (m, 1H), 2.76 (s, 2H), 2.02 (s, 1H), 1.84 (s, 1H), 1.64 (m,4H), 1.56 (t, J=14.5 Hz, 2H), 1.33 (dd, J=24.0, 10.8 Hz, 2H), 1.19 (m,4H), 1.02 (m, 2H). LCMS (ES⁺). (M+H)⁺=392.2.

Example 1.50 Synthesis ofN-tert-butyl-2-methyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 19)

Scheme 24 depicts a synthetic route for preparing an exemplary compound.

Step 1

In a vial was added 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine(150.00 mg; 0.79 mmol; 1.00 eq.), acetonitrile (3 ml),1-ethoxy-2-methyl-1-oxopropan-2-aminium chloride (159.62 mg; 0.95 mmol;1.20 eq.), and Hunig's base (0.58 mL; 3.33 mmol; 4.20 eq.). After beingstirred in a heat block at 60° C. for 15 h, the mixture was evaporatedand the residue was subjected to column chromatography eluting with (0to 50% EtOAc in Hexanes) to give ethyl2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}amino)-2-methylpropanoate(88 mg). LCMS (ES+): (M+H)⁺=283.9.

Step 2

In an round bottom flask was added ethyl2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}amino)-2-methylpropanoate(88.00 mg; 0.31 mmol; 1.00 eq.) in 1,4-dioxane (dry, ˜2 ml). The mixturewas purged with Ar. To the mixture was added 2-(tributylstannyl)pyridine(0.20 mL; 0.62 mmol; 2.00 eq.) and tetrakis(triphenylphosphane)palladium (35.84 mg; 0.03 mmol; 0.10 eq.) After being stirred in a heatblock at 108° C. for 15 h, the mixture was cooled and concentrated, andthe residue was purified by column chromatography (0-5% MeOH/DCM) togive Ethyl2-methyl-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanoate.LCMS (ES+): (M+H)⁺=327.0.

Step 3

Ethyl2-methyl-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanoate(67 mg; 0.21 mmol; 1 eq.) was dissolved in tetrahydrofuran (2 ml) andmethanol (0.5 ml). Lithium hydroxide (anhydrous, 25 mg; 1.03 mmol; 5eq.) was dissolved in water (˜0.8 ml) was added dropwise and stirred at25° C. After 4.5 h, the reaction was acidified carefully with 6 M HCl topH<3 and evaporated to dryness. The residue of2-methyl-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanoicacid hydrochloride was co-evaporated with toluene and dried under a highvacuum. This material was dissolved in N, N-dimethylformamide (3 ml) andcooled in an ice bath. Iodomethane (39 μL; 0.62 mmol; 3 eq.) andpotassium carbonate (142 mg; 1.03 mmol; 5 eq.) were added and themixture was stirred at 60° C. After 7 h, additional portions ofiodomethane and potassium carbonate were added several times to drivethe reaction to product. The reaction was taken up in ethyl acetate (50ml) and water (25 ml), the phases were separated, and the aqueous phasewas extracted with ethyl acetate (50 ml). The combined organics werewashed with water (10 ml) and sodium chloride solution (10 ml). Thecombined aqueous phases were extracted with 1:3 isopropanol chloroform(6×20 ml), combined with the organics, and dried over sodium sulfate.The residue from concentration was purified by reverse phasechromatography (Waters XSelect CSH C18 column, 0-80% acetonitrile/0.1%aqueous formic acid gradient) to give methyl2-methyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanoate(10 mg, 15%) as a yellow solid. LCMS (ES+): (M+H)⁺=327.0.

Step 4

Methyl2-methyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanoate(10 mg; 30.64 μmol; 1 eq.) was dissolved in tetrahydrofuran (0.5 ml) andmethanol (0.2 ml). Lithium hydroxide (anhydrous, 3.67 mg; 0.15 mmol; 5eq.) dissolved in water (˜0.2 ml) was added dropwise and the mixture wasstirred for 2 h at 25° C. The reaction was then acidified carefully with6 M HCl to pH<3 and evaporated to dryness. The residue was co-evaporatedwith toluene and dried under high vacuum. The residue of2-{4-[(1-carboxy-1-methylethyl)(methyl)amino]-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl}pyridin-1-iumchloride (10.7 mg; 0.03 mmol; 1 eq.) was dissolved inN,N-dimethylformamide (1.5 ml). N, N-diisopropylethylamine (19 μL; 0.11mmol; 3.5 eq.) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 23 mg; 0.06 mmol; 2 eq.) were added,followed by tert-butylamine (6 μL; 0.05 mmol; 1.5 eq.) After 15 h,additional portions of tert-butylamine, HATU and N,N-diisopropylethylamine were added to drive the reaction to completion.The reaction was partitioned into water (5 ml), ethyl acetate (50 ml)and sodium bicarbonate solution (10 ml). The phases were separated andthe aqueous phase was extracted with ethyl acetate (50 ml) and 1:3isopropanol:chloroform (50 ml). The combined organic phases were driedover sodium sulfate, evaporated, and purified by reverse phasechromatography (Waters XSelect CSH C18 column, 0-90% acetonitrile/0.1%aqueous formic acid gradient) to giveN-tert-butyl-2-methyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propenamide(6 mg, 50%) as a brown solid. LCMS (ES+): (M+H)⁺=368.1. ¹H NMR (400 MHz,Chloroform-d) δ 8.77-8.67 (m, 1H), 8.52-8.43 (m, 2H), 8.11-8.00 (m, 1H),7.74-7.65 (m, 1H), 6.79-6.71 (m, 1H), 4.73 (s, 3H), 3.00-2.91 (m, 4H),2.21-2.12 (m, 2H), 1.62 (s, 6H), 1.18 (s, 9H).

Example 1.51 Synthesis ofN-tert-butyl-2-{phenyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 20)

Scheme 25 depicts a synthetic route for preparing an exemplary compound.

Step 1

2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg; 1.06 mmol;1 eq.) was dissolved in acetonitrile (9.5 ml). Aniline (0.12 mL; 1.27mmol; 1.2 eq.) and N, N-diisopropylethylamine (0.55 mL; 3.17 mmol; 3eq.) were added. The reaction was sealed and heated in a microwavereactor at 120° C. for 1 h. Additional aniline (1.2 eq.) and N,N-diisopropylamine (1.5 eq.) were added and heating continued at 100° C.for 4 h, and then 90° C. in a heat block for 10 h. The reaction was thenconcentrated to approximately 2 ml in volume, more N,N-diisopropylethylamine (0.75 ml) was added, and heating continued at90° C. for 4 days. The reaction was evaporated and purified by silicagel chromatography (ethyl acetate/hexanes gradient) to give2-chloro-N-phenyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (194 mg, 74%)as a light-yellow film. LCMS (ES+): (M+H)⁺=245.9.

Step 2

2-Chloro-N-phenyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (60 mg; 0.24mmol; 1 eq.) was dissolved in N,N-dimethylformamide (1 ml). Potassiumcarbonate (67 mg; 0.49 mmol; 2 eq.) was added and the mixture wasstirred in a heat block at 50° C. for 2 h. The reaction mixture wascooled to 20° C. and 2-bromo-N-tert-butylpropanamide (76 mg; 0.37 mmol;1.5 eq.) in N,N-dimethylformamide (1 ml) was added and the reaction wasstirred at 80° C. for 24 h. Additional amounts of bromo-amide (38 mg)and potassium carbonate (33 mg) were added and the reaction was heatedfor 24 h more. The reaction mixture was taken up in ethyl acetate (50ml), water (10 ml), and sodium bicarbonate solution (10 ml). The phaseswere separated, and the aqueous phase was extracted with ethyl acetate(50 ml). The combined organics were washed with water (10 ml) and sodiumchloride solution (10 ml), dried over sodium sulfate, and evaporated.The residue was purified by silica gel chromatography (ethylacetate/hexanes gradient) to giveN-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(phenyl)amino)propenamide(48 mg, 52%) as a white solid. LCMS (ES+): (M+H)⁺=372.9.

Step 3

N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(phenyl)amino)propanamide(48 mg; 0.13 mmol; 1 eq.) was suspended in 1,4-dioxane (2 ml). Themixture was purged with Ar gas. 2-(Tributylstannyl)pyridine (0.08 mL;0.26 mmol; 2 eq.) and tetrakis(triphenylphosphane) palladium (15 mg;0.01 mmol; 0.1 eq.) were added and the mixture was stirred in a heatblock at 108° C. for 18 h. Additional amounts of tin reagent (0.08 ml)and palladium catalyst (15 mg) were added and heating continued for 14h. The reaction was evaporated, filtered, and purified by reverse phasechromatography (Waters XSelect CSH C18 column, 5-80% acetonitrile/0.1%aqueous formic acid gradient) to giveN-tert-butyl-2-{phenyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propenamide(19 mg, 35%) as a white solid. LCMS (ES+): (M+H)⁺=415.8. ¹H NMR (400MHz, Chloroform-d) δ 8.82 (d, J=4.8 Hz, 1H), 8.49 (d, J=8.0 Hz, 1H),7.92-7.83 (m, 1H), 7.43-7.33 (m, 4H), 7.33-7.26 (m, 2H), 7.26-7.21 (m,1H), 5.44 (s, 1H), 2.92 (t, J=7.8 Hz, 2H), 1.99-1.92 (m, 1H), 1.80-1.63(m, 3H), 1.33 (d, J=7.1 Hz, 3H), 1.19 (s, 9H).

Example 1.52 Synthesis of2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(quinolin-7-yl)acetamide(Compound 21)

Scheme 26 depicts a synthetic route for preparing an exemplary compound.

Into a 100-mL round-bottom flask, was placedN-methyl-N-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycine(250 mg, 0.879 mmol, 1.00 equiv), quinolin-7-amine (190.16 mg, 1.319mmol, 1.5 equiv), HATU (501.50 mg, 1.319 mmol, 1.50 equiv), DIEA (227.29mg, 1.759 mmol, 2 equiv), DCM (10.00 mL). The resulting solution wasstirred for 4 hr at room temperature. The resulting solution wasextracted with 3×20 mL of dichloromethane and the organic layers werecombined and dried over anhydrous sodium sulfate and concentrated undervacuum. The crude product was purified by Prep-HPLC with the followingconditions (2 #SHIMADZU (HPLC-01)): Column, Atlantis HILIC OBD Column,19*150 mm*5 um; mobile phase, Water (0.05% NH₃H₂O) and ACN (25% PhaseBup to 42% in 14 min. This resulted in 137.7 mg (38.2%) of2-(methyl(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)-N-(quinolin-7-yl)acetamideas an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.61 (s, 1H),8.86-8.80 (m, 1H), 8.67-8.60 (m, 1H), 8.39 (s, 1H), 8.32-8.22 (m, 2H),7.92 (d, J=8.8 Hz, 1H), 7.83-7.66 (m, 2H), 7.39 (td, J=7.6, 4.5 Hz, 2H),4.52 (s, 2H), 3.42 (s, 3H), 3.24 (t, J=7.3 Hz, 2H), 2.85 (t, J=7.8 Hz,2H), 2.02 (p, J=7.7 Hz, 2H). LCMS (ES) [M+1]⁺ m/z: 411.2.

Example 1.53 Synthesis ofN-(2-fluorophenyl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 22)

Scheme 27 depicts a synthetic route for preparing an exemplary compound.

Into a 50-mL round-bottom flask, was placed2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide(Intermediate I, 100.00 mg, 0.353 mmol, 1.00 equiv), dimethylformamide(8 mL), 2-fluoroaniline (39.22 mg, 0.353 mmol, 1.00 equiv), HATU (201.30mg, 0.529 mmol, 1.50 equiv) and DIEA (136.84 mg, 1.059 mmol, 3.00equiv). The resulting solution was stirred for 2 hr at 25° C. The crudereaction mixture was filtered and subjected to reverse phase preparativeHPLC (Prep-C18, 20-45M, 120 g, Tianjin Bonna-Agela Technologies;gradient elution of 30% MeCN in water to 40% MeCN in water over a 10 minperiod, water contains 0.1% FA) to provideN-(2-fluorophenyl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamideas a brown solid (45.7 mg, 34.31%). ¹H NMR (300 MHz, DMSO-d6) δ 10.05(s, 1H), 8.63 (d, J=4.4 Hz, 1H), 8.29 (d, J=7.8 Hz, 1H), 7.89-7.64 (m,2H), 7.47-7.34 (m, 1H), 7.32-7.20 (m, 1H), 7.14 (dt, J=6.4, 3.2 Hz, 2H),4.50 (s, 2H), 3.36-3.32 (m, 3H), 3.21 (t, J=7.4 Hz, 2H), 2.84 (t, J=7.8Hz, 2H), 2.01 (p, J=7.6 Hz, 2H). LCMS (ES) [M+1]⁺ m/z 378.2.

Example 1.54 Synthesis ofN-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4-yl]amino}acetamide(Compound 23)

Scheme 28 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 50-mL round-bottom flask, was placed a mixture of2,4-dichloro-5,6,7,8-tetrahydroquinazoline (300 mg, 1.477 mmol, 1.00equiv), MeOH (10.00 mL), N-tert-butyl-2-(methylamino)acetamide (319 mg,2.21 mmol, 1.50 equiv), and DIEA (286 mg, 2.21 mmol, 1.50 equiv). Theresulting solution was stirred for 16 hours at room temperature. Theresulting mixture was concentrated. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1/3). Thisresulted in 260 mg (56.62%) ofN-tert-butyl-2-[(2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino]acetamideas a white solid. LCMS (ES) [M+1]+ m/z: 311.

Step 2

Into a 40-mL vial purged and maintained in an inert atmosphere ofnitrogen, was placed a mixture ofN-tert-butyl-2-[(2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino]acetamide(200 mg, 0.643 mmol, 1.00 equiv), dioxane (15.0 mL),2-(tributylstannyl)pyridine (473 mg, 1.28 mmol, 2.00 equiv), andPd(PPh3)4 (223 mg, 0.193 mmol, 0.30 equiv). The resulting solution wasstirred for 16 hours at 110° C. The crude reaction mixture was filteredand subjected to reverse phase preparative MPLC (Prep-C18, 20-45 mM, 120g, Tianjin Bonna-Agela Technologies; gradient elution of 5% MeCN inwater to 26% MeCN in water over a 12 min period, where both solventscontain 0.1% formic acid). This resulted in 127.1 mg (55.88%) ofN-tert-butyl-2-[methyl[2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4-yl]amino]acetamideas an off-white solid. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.70 (d, J=4.3Hz, 1H), 8.37 (d, J=7.9 Hz, 1H), 7.93 (td, J=7.7, 1.8 Hz, 1H), 7.77 (s,1H), 7.52-7.47 (m, 1H), 4.04 (s, 2H), 3.21 (s, 3H), 2.83-2.79 (m, 2H),2.73-2.70 (m, 2H), 1.82-1.80 (m, 2H), 1.69-1.67 (m, 2H), 1.23 (s, 9H).LCMS (ES) [M+1]+ m/z: 354.2.

Example 1.55 Synthesis ofN-tert-butyl-2-{methyl[2-(4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 24)

Scheme 29 depicts a synthetic route for preparing an exemplary compound.

Into a 40-mL vial purged and maintained in an inert atmosphere ofnitrogen, was placedN-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(Intermediate II, 0.30 g, 1.01 mmol, 1.00 equiv), dioxane (15 mL),Pd(dppf)Cl₂·CH₂Cl₂ (0.22 g, 0.30 mmol, 0.30 equiv), and4-methyl-2-(tributylstannyl)-pyridine (0.58 g, 1.52 mmol, 1.50 equiv).The resulting solution was stirred overnight at 110° C. The resultingmixture was concentrated. The crude product was purified byFlash-Prep-HPLC with the following conditions (IntelFlash-1): Column,C18 silica gel; mobile phase, Phase A: Water (0.05% FA), Phase B CH₃CN(0-30% in 6 min); Detector, 220&254 nm. This resulted in 0.1 g crudeproduct. The crude product (0.1 g) was further purified by Prep-HPLCwith the following conditions: Column, X-Bridge C18 OBD, 5 um, 19*150mm; mobile phase, Phase A: Water (0.05% NH₄OH), Phase B CH₃CN (25% B upto 45% in 8 min); Detector, 220 nm; Flow rate 20 mL/min. This resultedin 88.9 mg (24.88%) of(N-tert-butyl)-2-(methyl(2-(4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino)acetamideas an off-white solid. ¹H-NMR: (300 MHz, DMSO-d6, ppm): δ 8.50 (d, J=4.9Hz, 1H), 8.16 (s, 1H), 7.71 (s, 1H), 7.26 (d, J=4.2 Hz, 1H), 4.14 (s,2H), 3.27 (s, 3H), 3.14 (t, J=7.2 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.41(s, 3H), 2.0-1.99 (m, 2H), 1.23 (s, 9H). LCMS: (ES, m/z): [M+H]⁺: 354.2.

Example 1.56 Synthesis of2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(1-methylcyclohexyl)acetamide(Compound 25)

Scheme 30 depicts a synthetic route for preparing an exemplary compound.

Into a 8-mL vial, was placed[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]aceticacid (Intermediate I, 150 mg, 0.53 mmol, 1.0 equiv), DMF (3.0 mL),1-methylcyclohexylamine (66 mg, 0.58 mmol, 1.1 equiv), and DIPEA (341mg, 2.64 mmol, 5.0 equiv). This was followed by the addition of HATU(301 mg, 0.79 mmol, 1.5 equiv) at 0° C. The mixture was stirred for 1 hat room temperature. The mixture was filtered, and the filtrate waspurified by Prep-HPLC with the following conditions: 120 g C₁₈ column,CH₃CN/H₂O (0.05% NH₄₀H), from 5% to 80% with 15 min, flow rate, 70mL/min, detector, 254 nm. 101.6 mg (51%) of2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]-N-(1-methylcyclohexyl)acetamidewas obtained as light yellow solid. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ8.66 (dd, J=4.7, 1.8 Hz, 1H), 8.34 (dt, J=8.0, 1.1 Hz, 1H), 7.86 (td,J=7.7, 1.8 Hz, 1H), 7.43 (ddd, J=7.5, 4.7, 1.2 Hz, 1H), 7.37 (s, 1H),4.20 (s, 2H), 3.28 (s, 3H), 3.16 (t, J=7.2 Hz, 2H), 2.82 (t, J=7.8 Hz,2H), 2.02-1.96 (m, 4H), 1.33-1.24 (m, 8H), 1.19 (s, 3H). LCMS: (ES,m/z): [M+H]⁺: 380.3.

Example 1.57 Synthesis of2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(oxan-3-yl)acetamide(Compound 26)

Scheme 31 depicts a synthetic route for preparing an exemplary compound.

Into an 8-mL vial, was placed[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]aceticacid (Intermediate I, 150 mg, 0.53 mmol, 1.0 equiv), DMF (3.0 mL),oxan-3-amine hydrochloride (80 mg, 0.58 mmol, 1.1 equiv), and DIEA (341mg, 2.64 mmol, 5.0 equiv). This was followed by the addition of HATU(301 mg, 0.79 mmol, 1.5 equiv) at 0° C. The mixture was stirred for 1 hat room temperature, filtered, and the filtrate was purified byPrep-HPLC with conditions: C18-120 g column, CH₃CN/H₂O (0.05% NH₄OH),from 5% to 80% with 15 min, flow rate, 70 mL/min, detector, 254 nm. Thisprovided 108.5 mg (56%) of2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]-N-(oxan-3-yl)acetamideas an off-white solid. ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 8.67 (d, J=4.2Hz, 1H), 8.29 (d, J=7.8 Hz, 1H), 8.09 (d, J=7.5 Hz, 1H), 7.90-7.85 (m,1H), 7.46-7.42 (m, 1H), 4.20 (s, 2H), 3.71-3.63 (m, 3H), 3.33-3.29 (m,1H), 3.26 (s, 3H) 3.15-3.05 (m, 3H), 2.82 (t, J=7.8 Hz, 2H), 2.04-1.94(m, 2H), 1.79-1.71 (m, 1H), 1.64-1.55 (m, 1H), 1.49-1.43 (m, 2H). LCMS:(ES, m/z): [M+H]⁺: 368.2.

Example 1.58 Synthesis ofN-benzyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 27)

Scheme 32 depicts a synthetic route for preparing an exemplary compound.

Into an 8-mL vial, was placed[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]aceticacid (200 mg, 0.70 mmol, 1.0 equiv), DMF (3.00 mL), benzylamine (83 mg,0.77 mmol, 1.1 equiv), and DIEA (455 mg, 3.52 mmol, 5.0 equiv). This wasfollowed by the addition of HATU (321 mg, 0.84 mmol, 1.2 equiv) at 0° C.The reaction solution was stirred for 1 h at room temperature, filtered,and the filtrate was purified by Prep-HPLC with conditions: C18-120 gcolumn, CH₃CN/H₂O (0.05% NH₄OH), from 5% to 80% with 15 min, flow rate,70 mL/min, detector, 254 nm. This provided 101.6 mg (39%) ofN-benzyl-2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamideas an off-white solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 8.64 (d, J=5.4Hz 2H), 8.26 (d, J=7.8 Hz, 1H), 7.83 (td, J=7.7, 1.9 Hz, 1H), 7.43 (dd,J=7.5, 4.9 Hz, 1H), 7.22-7.10 (m, 5H), 4.31 (s, 2H), 4.30 (s, 2H), 3.32(s, 3H), 3.17 (t, J=7.2 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.03-1.93 (m,2H). LCMS: (ES, m/z): [M+H]+: 374.2

Example 1.59 Synthesis ofN-tert-butyl-2-{[2-(5-hydroxypyrazin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 28)

Scheme 33 depicts a synthetic route for preparing an exemplary compound.

Into a 50-mL round-bottom flask, was placed a mixture ofN-(tert-butyl)-2-((2-(5-methoxypyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(120 mg, 0.324 mmol, 1.00 equiv), DCM (20.0 mL), and AlCl₃ (431 mg, 3.23mmol, 10.00 equiv). The resulting solution was stirred for 24 hours atroom temperature. The reaction was then quenched by the addition of 100mL of water/ice. The resulting solution was extracted with 3×50 mL ofdichloromethane. The organic layer was separated, dried over anhydrousmagnesium sulfate, and concentrated. The crude product was purified byPrep-HPLC with the following conditions: Column, Xbridge Prep C18 OBDColumn, 19×150 mm, 5 um; mobile phase, phase A: H₂O (0.05% NH₃H₂O);phase B: CH₃CN (10% CH₃CN up to 30% CH₃CN in 8 min). This resulted in57.2 mg (49.54%) ofN-(tert-butyl)-2-((2-(5-hydroxypyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆, ppm): δ12.63 (br, 1H), 8.26(br, 1H), 8.05 (d, J=1.3 Hz 1H), 7.61 (s, 1H), 4.08 (s, 2H), 3.3 (s,3H), 3.10 (t, J=7.3 Hz, 2H), 2.76 (t, J=7.8 Hz, 2H), 2.05-1.93 (m, 2H),1.24 (s, 9H). LCMS (ES) [M+1]⁺ m/z: 357.2.

Example 1.60 Synthesis ofN-cyclohexyl-1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azetidine-3-carboxamide(Compound 29)

Scheme 34 depicts a synthetic route for preparing an exemplary compound.

Step 1

To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine(300.00 mg; 1.59 mmol; 1.00 eq.) and methyl1-chloroazetidine-3-carboxylate HCl salt (300.71 mg; 1.98 mmol; 1.25eq.) in AcCN (4 mL) was added triethylamine (0.44 mL; 3.17 mmol; 2.00eq.) at room temperature. The reaction mixture was stirred for 30 min atroom temperature and 3 h at 75° C. The resulting mixture was cooled anddiluted with water and EtOAc. The organic layer was collected and wasconcentrated, and the resulting residue was purified by columnchromatography (Hexanes/EtOAc=30:70) to give methyl1-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}azetidine-3-carboxylate(390 mg). LCMS (ES⁺): (M+H)⁺=268.1, 270.1.

Step 2

To a solution of methyl1-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}azetidine-3-carboxylate(390.00 mg; 1.46 mmol; 1.00 eq.) in THF (2 mL) was added MeOH (1 mL) andwater (1 mL), followed by lithium hydroxide monohydrate (122.26 mg; 2.91mmol; 2.00 eq.). The mixture was stirred for 2 h and concentrated andthe residue was acidified with 1N HCl to pH=3. The resultingprecipitates were collected by filtration to give1-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}azetidine-3-carboxylicacid (339 mg). LCMS (ES⁺): (M+H)⁺=254.0, 256.2.

Step 3

To a solution of1-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}azetidine-3-carboxylicacid (156.00 mg; 0.61 mmol; 1.00 eq.) and cyclohexanamine (0.11 mL; 0.92mmol; 1.50 eq.) in DMF (2 mL) was added DIPEA (0.27 mL; 1.54 mmol; 2.50eq.) and HATU (257.20 mg; 0.68 mmol; 1.10 eq.). The reaction was stirreduntil completion, and the mixture was poured over Sat. NaHCO₃ and water.The resulting precipitates were collected by filtration to give1-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}-N-cyclohexylazetidine-3-carboxamide(198 mg). LCMS (ES⁺): (M+H)⁺=335.0, 337.1.

Step 4

To a suspension of1-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}-N-cyclohexylazetidine-3-carboxamide(100.00 mg; 0.30 mmol; 1.00 eq.) in DMF (2 mL) was added2-(tributylstannyl)pyridine (164.92 mg; 0.45 mmol; 1.50 eq.) andtetrakis(triphenylphosphane) palladium (34.51 mg; 0.03 mmol; 0.10 eq.).The mixture was heated at 115° C. for 15 h, the mixture was cooled anddiluted with water and AcCN, the insoluble material was filtered off,and the filtrate was purified by preparative HPLC to giveN-cyclohexyl-1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azetidine-3-carboxamide(63 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (ddd, J=4.8, 1.8, 0.9 Hz, 1H),8.25 (dt, J=7.9, 1.2 Hz, 1H), 7.89 (td, J=7.7, 1.8 Hz, 2H), 7.45 (ddd,J=7.6, 4.7, 1.2 Hz, 1H), 4.33 (t, J=8.6 Hz, 2H), 4.24 (t, J=7.4 Hz, 2H),3.58-3.50 (m, 1H), 3.48-3.39 (m, 1H), 2.93 (t, J=7.4 Hz, 2H), 2.81 (t,J=7.8 Hz, 2H), 2.01 (p, J=7.7 Hz, 2H), 1.77-1.62 (m, 4H), 1.53 (d,J=12.3 Hz, 1H), 1.32-1.03 (m, 5H). LCMS (ES⁺): (M+H)⁺=378.3.

Example 1.61 Synthesis ofN-cyclohexyl-1-[2-(4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azetidine-3-carboxamide(Compound 30)

Compound 30 was synthesized similar to Compound 29 by replacing2-(tributylstannyl)pyridine with 4-methyl-2-(tributylstannyl)pyridine.¹H NMR (400 MHz, DMSO-d₆) δ 8.51-8.46 (m, 1H), 8.06 (dd, J=1.8, 0.9 Hz,1H), 7.88 (d, J=7.8 Hz, 1H), 7.27-7.21 (m, 1H), 4.29 (t, J=8.5 Hz, 2H),4.21 (t, J=7.3 Hz, 2H), 3.60-3.48 (m, 1H), 3.48-3.38 (m, 1H), 2.92 (t,J=7.4 Hz, 2H), 2.78 (t, J=7.8 Hz, 2H), 2.37 (s, 3H), 1.99 (p, J=7.7 Hz,2H), 1.77-1.73 (m, 2H), 1.66 (dt, J=12.6, 3.7 Hz, 2H), 1.53 (d, J=12.8Hz, 1H), 1.33-1.18 (m, 2H), 1.22-1.03 (m, 3H). LCMS (ES+): (M+H)⁺=392.4.

Example 1.62 Synthesis ofN-(1-methyl-2-oxopyrrolidin-3-yl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 31)

Compound 31 was synthesized similar to compound 75 by replacing4-methoxyaniline with 3-amino-1-methylpyrrolidin-2-one. LCMS (ES+):(M+H)⁺=381.3. ¹H NMR (400 MHz, Acetonitrile-d3) δ 8.60-8.55 (m, 1H),8.37 (d, J=8.0 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.90-7.84 (m, 1H), 7.40(ddd, J=7.6, 4.8, 1.2 Hz, 1H), 4.43 (q, J=9.0 Hz, 1H), 4.31-4.10 (m,2H), 3.34 (s, 3H), 3.23-3.14 (m, 4H), 2.89-2.85 (m, 2H), 2.74 (s, 3H),2.28 (dddd, J=12.5, 9.0, 6.9, 2.2 Hz, 1H), 2.10-1.99 (m, 2H), 1.79-1.67(m, 1H).

Example 1.63 Synthesis ofN-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 32)

Compound 32 was synthesized similar to compound 75 by replacing4-methoxyaniline with 2,2-difluoro-1,3-benzodioxol-5-amine. LCMS (ES+):(M+H)⁺=440.3. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.91 (s, 1H), 8.68 (d,J=4.7 Hz, 1H), 8.39 (d, J=8.0 Hz, 1H), 7.92-7.84 (m, 1H), 7.69 (d, J=2.1Hz, 1H), 7.46 (dd, J=7.6, 4.9 Hz, 1H), 7.24 (dd, J=8.7, 2.1 Hz, 1H),7.07 (d, J=8.7 Hz, 1H), 4.35 (s, 2H), 3.43 (s, 3H), 3.28-3.22 (m, 2H),2.96-2.90 (m, 2H), 2.11-2.06 (m, 2H).

Example 1.64 Synthesis ofN-tert-butyl-2-{[2-(pyrimidin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 33)

Scheme 35 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 500-mL round-bottom flask, was placed a mixture ofpyrimidine-2-carboximidamide hydrochloride (10.0 g, 63.0 mmol, 1.00equiv), MeOH (200 mL), ethyl 2-oxocyclopentane-1-carboxylate (14.7 g,94.5 mmol, 1.50 equiv), and NaOMe (6.81 g, 126 mmol, 2.00 equiv). Theresulting solution was stirred for 16 hours at 60° C. The resultingmixture was concentrated. The reaction was then quenched by the additionof 200 mL of water. The pH value of the solution was adjusted to 3 withHCl (2 mol/L). The resulting solution was extracted with 3×150 mL ofdichloromethane, the organic layers were separated and combined, driedover anhydrous sodium sulfate, and concentrated. This resulted in 1.1 g(8.14%) of2-(pyrimidin-2-yl)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one asan off-white oil. LCMS (ES) [M+1]+ m/z: 215.

Step 2

Into a 20-mL vial was placed2-(pyrimidin-2-yl)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one(1.00 g, 4.66 mmol, 1.00 equiv) and phosphorus oxychloride (10 mL). Theresulting solution was stirred for 4 hours at 100° C. The resultingmixture was concentrated. The reaction was then quenched by the additionof 50 mL of water. The pH value of the solution was adjusted to 9 withsaturated sodium carbonate solution. The resulting solution wasextracted with 3×50 mL of dichloromethane, the organic layer wasseparated and dried in an oven under reduced pressure. This resulted in560 mg (51.56%) of4-chloro-2-(pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine asblack oil. LCMS (ES) [M+1]+ m/z: 233.

Step 3

Into a 40-mL vial was placed4-chloro-2-(pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (500mg, 2.14 mmol, 1.00 equiv), MeOH (10.0 mL),2-amino-N-tert-butylacetamide (419 mg, 3.22 mmol, 1.50 equiv) and DIEA(416 mg, 3.22 mmol, 1.50 equiv). The resulting solution was stirred for16 hours at 80° C. The resulting mixture was concentrated. The crudeproduct was purified by Prep-HPLC with the following conditions: Column,SunFire Prep C18 OBD Column, 19×150 mm, 5 um; mobile phase, phase A: H2O(0.1% FA); phase B: CH3CN (5% CH3CN up to 35% CH3CN in 10 min). Thisresulted in 111 mg (15.82%) ofN-(tert-butyl)-2-((2-(pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[d]Pyrimidin-4-yl)amino)acetamide.1H NMR (300 MHz, DMSO-d6, ppm): δ 8.91 (d, J=4.9 Hz, 2H), 7.63 (s, 1H),7.56 (t, J=4.9 Hz, 1H), 7.08 (t, J=5.8 Hz, 1H), 3.97 (d, J=5.8 Hz, 2H),2.84 (t, J=7.7 Hz, 2H), 2.76 (t, J=7.4 Hz, 2H), 2.10-2.05 (m, 2H), 1.22(s, 9H). LCMS (ES) [M+1]+ m/z: 327.2.

Example 1.65 Synthesis ofN-tert-butyl-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 34)

Scheme 36 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 100-mL 3-necked round-bottom flask purged and maintained in aninert atmosphere of argon, was placed 2-chloro-4-methoxypyridine (500mg, 3.48 mmol, 1.00 equiv), hexamethyldistannane (1.48 g, 4.527 mmol,1.3 equiv), dioxane (20 mL), and Pd(PPh₃)₄ (804 mg, 0.69 mmol, 0.2equiv). The resulting solution was stirred for 16 h at 110° C. in an oilbath. The solids were filtered out. The filtrate was concentrated togive 950 mg of 4-methoxy-2-(trimethylstannyl)pyridine. The crude productwas used for next step without further purification. LCMS (ES) [M+1]⁺m/z: 274.02.

Step 2

Into a 100-mL 3-necked round-bottom flask purged and maintained in aninert atmosphere of argon, was placed4-methoxy-2-(trimethylstannyl)pyridine (947 mg, 3.48 mmol, 1.00 equiv),N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(Intermediate II, 310 mg, 1.04 mmol, 0.3 equiv), Pd(dppf)Cl₂ (254 mg,0.35 mmol, 0.1 equiv) and dioxane (15 mL). The resulting solution wasstirred for 16 hr at 100° C. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:50 to 3:1). The crude product (160 mg)was purified by Flash-Prep-HPLC. This resulted in 50 mg (3.9%) ofN-tert-butyl-2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (d, J=5.4 Hz, 1H),7.86 (d, J=2.4 Hz, 1H), 7.69 (s, 1H), 7.06 (dd, J=5.7, 2.4 Hz, 1H), 4.14(s, 2H), 3.92 (s, 3H), 3.27 (s, 3H), 3.14 (t, J=7.2 Hz, 2H), 2.82 (t,J=7.8 Hz, 2H), 1.99 (t, J=7.5 Hz, 2H), 1.23 (s, 9H). LCMS (ES) [M+1]⁺m/z: 370.2.

Example 1.66 Synthesis ofN-tert-butyl-2-({2-[4-(methoxymethyl)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 35)

Scheme 37 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed (2-chloropyridin-4-yl)methanol (5.00g, 34.826 mmol, 1.00 equiv), THE (20 mL). The resulting solution wasstirred for 40 min at 0° C., and NaH (1.25 g, 52.088 mmol, 1.50 equiv)was added. The resulting solution was allowed to stir for an additional4 hr at room temperature. The reaction was quenched by the addition ofwater. The resulting mixture was extracted with ethyl acetate (3×30 mL),the organic layers were combined, dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified by silica gelcolumn chromatography with ethyl acetate/petroleum ether (1:4). Thisresulted in 3.1 g (56.5%) of 2-chloro-4-(methoxymethyl)pyridine as alight yellow solid. LCMS (ES) [M+1]⁺ m/z: 158.

Step 2

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed 2-chloro-4-(methoxymethyl)pyridine(1.00 g, 6.345 mmol, 1.00 equiv), hexamethyldistannane (2.49 g, 7.600mmol, 1.20 equiv), Pd(dppf)Cl₂ (0.93 g, 0.001 mmol, 0.2 equiv), anddioxane (20.00 mL). The resulting solution was stirred for 4 hr at 100°C. The solution was cooled and concentrated and the resulting4-(methoxymethyl)-2-(trimethylstannyl)pyridine was used for next stepdirectly. LCMS (ES) [M+1]⁺ m/z: 288.

Step 3

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed4-(methoxymethyl)-2-(trimethylstannyl)pyridine (Intermediate II, 500.00mg, 1.748 mmol, 1.00 equiv),N-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(415.16 mg, 1.399 mmol, 0.8 equiv), Pd(dppf)Cl₂ (255.87 mg, 0.350 mmol,0.20 equiv), and dioxane (20.00 mL). The resulting solution was stirredfor 16 seconds at 100° C. The resulting solution was cooled andextracted with ethyl acetate (3×20 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, and concentrated undervacuum. The crude product was purified by Prep-HPLC with the followingconditions (2 #SHIMADZU (HPLC-01)): Column, Welch Xtimate C18, 21.2*250mm, 5 um; mobile phase, Water (0.05% TFA) and MeOH:ACN=1:1 (10% PhaseBup to 60% in 17 min. This resulted in 51.2 mg (7.6%) ofN-(tert-butyl)-2-((2-(4-(methoxymethyl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a pink solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.83 (dd, J=5.0, 0.8 Hz,1H), 8.46-8.39 (m, 1H), 7.97 (s, 1H), 7.73 (dd, J=5.0, 1.7 Hz, 1H), 4.64(s, 2H), 4.41 (s, 2H), 3.49 (s, 3H), 3.42 (s, 3H), 3.32-3.18 (m, 2H),3.07 (t, J=7.9 Hz, 2H), 2.11 (p, J=7.7 Hz, 2H), 1.25 (s, 9H). LCMS (ES)[M+1]⁺ m/z: 384.2.

Example 1.67 Synthesis ofN-tert-butyl-2-{ethyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 36)

Scheme 38 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 50-mL round-bottom flask, was placed a solution ofN-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide(500.00 mg, 1.768 mmol, 1.00 equiv) in DMF (10 mL), ethyl iodide (303.36mg, 1.945 mmol, 1.1 equiv) and K₂CO₃ (366.57 mg, 2.652 mmol, 1.5 equiv).The resulting solution was stirred for 3 hr at room temperature. Theresulting solution was diluted with 50 mL of H₂O and extracted with 2×50mL of ethyl acetate. Organic layers were combined, dried over anhydroussodium sulfate, and concentrated under vacuum. This resulted in 390 mg(78.00%) ofN-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(ethyl)amino)acetamideas a light yellow solid. LCMS (ES) [M+1]⁺ m/z: 311.

Step 2

Into a 25-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen was placed a solution ofN-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(ethyl)amino)acetamide(230.00 mg, 0.813 mmol, 1.00 equiv) in Tol (8 mL),2-(tributylstannyl)pyridine (359.34 mg, 0.976 mmol, 1.2 equiv) andPd(PPh₃)₄ (93.99 mg, 0.081 mmol, 0.1 equiv). The resulting solution wasstirred for 12 hr at 100° C. in an oil bath. The resulting solution wasdiluted with 10 mL of H₂O and extracted with 2×15 mL of ethyl acetate.Organic layers were combined, dried over anhydrous sodium sulfate, andconcentrated. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:1). The collected crude product wasfurther purified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, C18 silica gel; mobile phase, CAN:H₂O=1:20increasing to ACN:H₂O=1:4 within 15; Detector, 254 nm. product wasobtained and concentrated. This resulted in 120 mg (41.74%) ofN-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(ethyl)amino)acetamideas a solid. ¹H NMR (300 MHz, DMSO-d₆) δ8.67 (dd, J=4.8, 1.9 Hz, 1H),8.35 (d, J=8.1 Hz, 1H), 7.88 (td, J=7.7, 1.9 Hz, 1H), 7.71 (s, 1H), 7.44(ddd, J=7.5, 4.7, 1.2 Hz, 1H), 4.10 (s, 2H), 3.66 (q, J=7.1 Hz, 2H),3.09 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.08-1.95 (m, 2H), 1.23(s, 9H), 1.19 (t, J=7.0 Hz, 3H). LCMS (ES) [M+1]⁺ m/z 354.2.

Example 1.68 Synthesis ofN-tert-butyl-2-[(2-hydroxyethyl)[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide(Compound 37)

Scheme 39 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 25-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placedN-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide.The resulting solution was stirred for 12 hr at room temperature in anoil bath. The resulting solution was diluted with 25 mL of H₂O. Theresulting solution was extracted with 2×25 mL of ethyl acetate, driedover anhydrous sodium sulfate, and concentrated. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:3). Thecollected fractions were combined and concentrated. This resulted in 420mg (57.8%) ofN-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)amino)acetamide.LCMS (ES) [M+1]⁺ m/z: 411.

Step 2

Into a 25-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed a solution ofN-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)amino)acetamide(400 mg, 0.97 mmol, 1.00 equiv) in dioxene (8 mL),2-(tributylstannyl)pyridine (243 mg, 0.97 mmol, 1 equiv), and Pd(PPh₃)₄(112 mg, 0.097 mmol, 0.1 equiv). The resulting solution was stirred for12 hr at 100° C. in an oil bath. The resulting solution was diluted with20 mL of H₂O and extracted with 3×20 mL of ethyl acetate. The organiclayers were combined and concentrated. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:1). Thecollected fractions were combined and concentrated. This resulted in 230mg (52.09%) ofN-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(ethyl)amino)acetamideas a solid. LCMS (ES) [M+1]⁺ m/z: 454.

Step 3

Into a 25-mL round-bottom flask, was placed a solution ofN-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(ethyl)amino)acetamide(150.00 mg, 0.331 mmol, 1.00 equiv) in MeOH (7 mL), pTSA (5.69 mg, 0.033mmol, 0.1 equiv). The resulting solution was stirred for 12 hr at roomtemperature. The resulting mixture was concentrated. The crude productwas purified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, silica gel; mobile phase, ACN:H₂O (0.01%TFA)=1:15 increasing to ACN:H₂O (0.01% TFA)=1:3 within 9; Detector, UV254 nm. This resulted in 80 mg (65.48%) ofN-(tert-butyl)-2-((2-hydroxyethyl)(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide.LCMS (ES) [M+1]⁺ m/z: 370.2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.67 (d, J=4.9Hz, 1H), 8.36 (d, J=7.9 Hz, 1H), 7.93-7.80 (m, 2H), 7.48-7.40 (m, 1H),5.15 (t, J=5.5 Hz, 1H), 4.16 (s, 2H), 3.78-3.61 (m, 4H), 3.10 (t, J=7.3Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.06-1.96 (m, 2H), 1.22 (s, 9H).

Example 1.69 Synthesis of2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-[(pyridin-2-yl)methyl]acetamide(Compound 38)

Scheme 40 depicts a synthetic route for preparing an exemplary compound.

Into an 8-mL vial was placed[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]aceticacid (200 mg, 0.70 mmol, 1.0 equiv), DMF (3.0 mL), 2-pyridinemethanamine(84 mg, 0.77 mmol, 1.1 equiv), and DIEA (455 mg, 3.52 mmol, 5.0 equiv).This was followed by the addition of HATU (401 mg, 1.06 mmol, 1.5 equiv)at 0° C. The mixture was stirred for 1 h at room temperature, filtered,and the filtrate was purified by Prep-HPLC with conditions: C18-120 gcolumn, CH₃CN/H₂O (0.05% NH₄OH), from 5% to 80% with 15 min, flow rate,70 mL/min, detector, 254 nm. This resulted in 62.8 mg (24%) of2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]-N-(pyridin-2-ylmethyl)acetamideformate as light brown solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ8.72 (t,J=6.0 Hz, 1H), 8.64 (dd, J=4.7, 1.8 Hz, 1H), 8.43 (dd, J=4.8, 1.9 Hz,1H), 8.28 (dt, J=8.0, 1.1 Hz, 1H), 8.16 (s, 1H), 7.85 (td, J=7.7, 1.8Hz, 1H), 7.44 (ddd, J=7.5, 4.7, 1.2 Hz, 1H), 7.35 (td, J=7.7, 1.8 Hz,1H), 7.21-7.14 (m, 2H), 4.37 (d, J=6.0 Hz, 2H), 4.34 (s, 2H), 3.34 (s,3H), 3.20 (t, J=7.2 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 1.99 (p, J=7.7 Hz,2H). LCMS: (ES, m/z): [M+H]+: 375.2.

Example 1.70 Synthesis ofN-tert-butyl-2-({2-[6-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 39)

Scheme 41 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 100-mL round-bottom flask, was placed 6-chloropyridin-2-ol (5.00g, 38.59 mmol, 1.00 equiv), DMF (50.0 mL), 2-(2-bromoethoxy)oxane (9.68g, 46.31 mmol, 1.20 equiv), and K₂CO₃ (10.67 g, 77.19 mmol, 2.00 equiv).The mixture was stirred for 2 h at 70° C. The reaction mixture wascooled and diluted with 200 mL of H₂O, and extracted with 3×50 mL ofethyl acetate. The organic layers were combined and dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel column withethyl acetate/petroleum ether (1/3) to give 9.0 g (90%) of2-chloro-6-[2-(oxan-2-yloxy)ethoxy]pyridine as colorless oil. LCMS (ES)[M+1]⁺ m/z: 258.

Step 2

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen was placed2-chloro-6-[2-(oxan-2-yloxy)ethoxy]pyridine (600 mg, 2.42 mmol, 1.00equiv), dioxane (10.0 mL), hexamethyldistannane (872 mg, 2.66 mmol, 1.10equiv) and Pd(dppf)Cl₂ (177 mg, 0.24 mmol, 0.10 equiv). The mixture wasstirred for 2 h at 100° C. The reaction mixture was cooled and dilutedwith 20 mL of H₂O, and extracted with 3×10 mL of ethyl acetate. Theorganic layers were combined and dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Thisresulted in 500 mg of2-[2-(oxan-2-yloxy)ethoxy]-6-(trimethylstannyl)pyridine as brown oil andthe crude product was used to the next step directly withoutpurification. LCMS (ES) [M+1]⁺ m/z: 388.

Step 3

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed2-[2-(oxan-2-yloxy)ethoxy]-6-(trimethylstannyl)pyridine (468 mg, 1.21mmol, 1.20 equiv), dioxane (5.0 mL),N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(300 mg, 1.01 mmol, 1.00 equiv), and Pd(PPh₃)₄ (116 mg, 0.10 mmol, 0.10equiv). The mixture was stirred for 16 h at 100° C. The reaction mixturewas cooled and diluted with 20 mL of EA, filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column with ethyl acetate/petroleum ether (4/1). This resulted in400 mg (82%) ofN-tert-butyl-2-[methyl(2-[6-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamideas brown solid. LCMS (ES) [M+1]⁺ m/z: 484.

Step 4

Into a 100-mL round-bottom flask was placedN-tert-butyl-2-[methyl(2-[6-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(400 mg, 0.82 mmol, 1.00 equiv), MeOH (5.0 mL), and TsOH (142 mg, 0.82mmol, 1.00 equiv). The resulting solution was stirred for 1 h at roomtemperature. The resulting mixture was concentrated and diluted with 5mL of H₂O. The pH value of the solution was adjusted to 8 with NH₃·H₂O(30%). The mixture was extracted with 3×5 mL of ethyl acetate, theorganic layers were combined, dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated. The residue was purified byPrep-HPLC with the following conditions: Column, Welch XB-C18, 21.2*250mm, 5 um, Mobile phase, Water (0.05% NH₄OH) and CH₃CN (10% Phase B up to65% in 15 min), Detector, UV 254 nm. This resulted in 121.1 mg (36.6%)ofN-tert-butyl-2-([2-[6-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamideas white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.96 (d, J=7.2 Hz, 1H), 7.79(t, J=7.8 Hz, 1H), 7.63 (s, 1H), 6.89 (d, J=8.1 Hz, 1H), 5.18 (br, 1H),4.43-4.39 (m, 2H), 4.16 (s, 2H), 3.79-3.75 (m, 2H), 3.27 (s, 3H), 3.13(t, J=7.5 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.04-1.96 (m, 2H), 1.23 (s,9H). LCMS (ES) [M+1]⁺ m/z: 400.2.

Example 1.71 Synthesis ofN-tert-butyl-2-({2-[5-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 40)

Scheme 42 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 250-mL round-bottom flask was placed 6-bromopyridin-3-ol (2.00 g,11.49 mmol, 1.00 equiv), DMF (30.00 mL), 2-(2-bromoethoxy)oxane (2.88 g,13.79 mmol, 1.20 equiv), and K₂CO₃ (3.18 g, 22.99 mmol, 2.00 equiv). Theresulting solution was stirred for 2 h at 70° C. The reaction mixturewas cooled to room temperature. The reaction was then quenched by theaddition of 50 mL of water. The resulting mixture was extracted with3×50 mL of ethyl acetate, the organic layers were combined, dried overanhydrous sodium sulfate, and concentrated. The residue was applied ontoa silica gel column with ethyl acetate/petroleum ether (15%). Thisresulted in 3.2 g (92.13%) of 2-bromo-5-[2-(oxan-2-yloxy)ethoxy]pyridineas a yellow oil. LCMS (ES) [M+H]+ m/z: 302.

Step 2

Into a 100-mL round-bottom flask, was placed2-bromo-5-[2-(oxan-2-yloxy)ethoxy]pyridine (1.00 g, 3.31 mmol, 1.00equiv), hexamethyldistannane (1.30 g, 3.97 mmol, 1.20 equiv), Pd(PPh3)4(0.38 g, 0.33 mmol, 0.1 equiv), and dioxane (10.00 mL). The resultingsolution was stirred for 3 h at 100° C. The reaction mixture was cooledto room temperature and was addedN-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(Intermediate II, 0.49 g, 1.65 mmol, 0.50 equiv) and Pd(dppf)Cl₂ (0.24g, 0.33 mmol, 0.10 equiv). The resulting solution was stirred for 5 h at100° C. The reaction mixture was cooled to room temperature. The crudeproduct (1 g) was purified by Prep-HPLC with the following conditions:Column, XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um; mobile phase,Water (0.1% NH4HCO3) and CAN (30% Phase B up to 60% in 11 min);Detector, 254 nm. This resulted in 150 mg (9.37%) ofN-tert-butyl-2-[methyl(2-[5-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamideas yellow solid. LCMS (ES) [M+H]+ m/z: 484.

Step 3

Into an 8-mL vial was placedN-tert-butyl-2-[methyl(2-[5-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(150.00 mg, 0.31 mmol, 1.00 equiv), MeOH (5.00 mL) and PTSA (10.68 mg,0.06 mmol, 0.20 equiv). The resulting solution was stirred for 1 h atroom temperature. The crude product (150 mg) was purified by Prep-HPLCwith the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150 mm, 5 um; mobile phase, Water (0.1% NH₄HCO₃) and CAN (20% PhaseB up to 50% in 11 min); Detector, 254 nm. This resulted in 45.0 mg(36.32%) ofN-tert-butyl-2-([2-[5-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamideas a white solid. 1H-NMR (300 MHz, DMSO-d6) δ 8.38-8.27 (m, 2H), 7.68(s, 1H), 7.43 (dd, J=8.8, 3.0 Hz, 1H), 4.94 (t, J=5.5 Hz, 1H), 4.18-4.09(m, 4H), 3.78-3.73 (m, 2H), 3.25 (s, 3H), 3.12 (t, J=7.3 Hz, 2H), 2.79(t, J=7.8 Hz, 2H), 2.10-1.89 (m, 2H), 1.24 (s, 9H). LCMS: (ES, m/z):[M+H]+: 400.3.

Example 1.72 Synthesis ofN-tert-butyl-2-({2-[4-(hydroxymethyl)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 41)

Scheme 43 depicts a synthetic route for preparing an exemplary compound.

Into a 50-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placedN-(tert-butyl)-2-((2-(4-(methoxymethyl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(100 mg, 0.261 mmol, 1.00 equiv), BBr₃ (0.78 mL, 0.780 mmol, 2.99equiv), and DCM (10.00 mL). The resulting solution was stirred for 4 hrat −78° C. The reaction was quenched by the addition of water. Theresulting solution was extracted with dichloromethane (3×20 mL), theorganic layers were combined, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The crude product was purified by Prep-HPLCwith the following conditions (2 #SHIMADZU (HPLC-01)): Column, WelchXB-C18, 21.2*250 mm, 5 um; mobile phase, Water (0.05% NH₃H₂O) and AcCN(5% Phase B up to 50% in 16 min). This resulted in 30.2 mg (31.4%) ofN-(tert-butyl)-2-((2-(4-(hydroxymethyl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (d, J=4.9 Hz, 1H),8.26 (s, 1H), 7.68 (s, 1H), 7.39 (d, J=5.0 Hz, 1H), 5.48 (br, 1H), 4.62(s, 2H), 4.16 (s, 2H), 3.32 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.82 (t,J=7.8 Hz, 2H), 1.99 (p, J=7.5 Hz, 2H), 1.24 (s, 9H). LCMS (ES) [M+1]⁺m/z: 370.2.

Example 1.73 Synthesis ofN-tert-butyl-2-{methyl[2-(4-methylpyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4-yl]amino}acetamide(Compound 42)

Scheme 44 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 40-mL vial, was placed 2,4-dichloro-5,6,7,8-tetrahydroquinazoline(500.00 mg, 2.46 mmol, 1.00 equiv), CH₃CN (8.00 mL), DIEA (636.45 mg,4.92 mmol, 2.00 equiv), and N-tert-butyl-2-(methylamino)acetamide(390.60 mg, 2.71 mmol, 1.10 equiv). The resulting solution was stirredfor 3 h at 80° C. The reaction mixture was cooled to room temperature.The crude product (1 g) was purified by Prep-HPLC with the followingconditions: Column, XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um;mobile phase, Water (0.1% NH₄HCO₃) and CAN (30% Phase B up to 60% in 11min); Detector, 254. This resulted in 410 mg (53.57%) ofN-tert-butyl-2-[(2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino]acetamideas a white solid. LCMS (ES) [M+H]⁺ m/z: 311.

Step 2

Into a 40-mL vial purged and maintained in an inert atmosphere ofnitrogen, was placedN-tert-butyl-2-[(2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino]acetamide(350.00 mg, 1.12 mmol, 1.00 equiv), 4-methyl-2-(tributylstannyl)pyridine(559.44 mg, 1.46 mmol, 1.30 equiv), and dioxane (8.00 mL), Pd(dppf)Cl₂(82.39 mg, 0.11 mmol, 0.10 equiv). The resulting solution was stirredfor overnight at 110° C. The reaction mixture was cooled to roomtemperature. The resulting mixture was concentrated. The crude product(500 mg) was purified by Prep-HPLC with the following conditions:Column, XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um; mobile phase,Water (0.1% NH₄HCO₃) and CAN (30% Phase B up to 60% in 11 min);Detector, 254. This resulted in 86.4 mg (20.88%) ofN-tert-butyl-2-[methyl[2-(4-methylpyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4-yl]amino]acetamideas an off-white solid. ¹H-NMR (300 MHz, DMSO-d6) δ 8.51 (d, J=4.9 Hz,1H), 8.15 (d, J=1.6 Hz, 1H), 7.77 (s, 1H), 7.31-7.23 (m, 1H), 3.99 (s,2H), 3.15 (s, 3H), 2.78 (t, J=6.4 Hz, 2H), 2.69 (t, J=6.0 Hz, 2H), 2.40(s, 3H), 1.82 (s, 2H), 1.68 (d, J=6.9 Hz, 2H), 1.22 (s, 9H). LCMS (ES,m/z): [M+H]⁺: 368.2.

Example 1.74 Synthesis ofN-tert-butyl-2-({2-[5-(2-hydroxyethyl)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 43)

Scheme 45 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 250-mL 3-necked round-bottom flask, was placed(6-chloropyridin-3-yl)acetic acid (5.0 g, 29.14 mmol, 1.0 equiv), THE(50.0 mL). This was followed by the addition of B₂H₆ (1 M in THF) (88.0mL, 3.0 eq) at 0° C. After addition, the mixture was stirred for 12 h atroom temperature. The reaction was then quenched by the addition of MeOH(30 mL), diluted with of H₂O (100 mL), and extracted with 3×100 mL ofdichloromethane. The combined organic phase was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. This resulted in 3.09 g (67%) of2-(6-chloropyridin-3-yl)ethanol as yellow oil. LCMS (ES) [M+1]⁺ m/z:158.

Step 2

Into a 100-mL round-bottom flask, was placed2-(6-chloropyridin-3-yl)ethanol (3.09 g, 19.61 mmol, 1.0 equiv), DCM(30.0 mL), DHP (3.30 g, 39.23 mmol, 2.0 equiv), and TsOH (340 mg, 1.97mmol, 0.10 equiv). The reaction solution was stirred for 2 h at roomtemperature. The mixture was diluted with of saturated Na₂CO₃ (20.0 mL),and extracted with 3×50 mL of dichloromethane. The combined organicphase was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column with ethyl acetate/petroleum ether (7%).This resulted in 3.0 g (63%) of2-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridine as a yellowoil. LCMS (ES) [M+1]⁺ m/z: 242.

Step 3

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed2-chloro-5-[2-(oxan-2-yloxy)ethyl]pyridine (1.17 g, 4.84 mmol, 1.0equiv), dioxane (30.0 mL), hexamethyldistannane (1.60 g, 4.88 mmol, 1.0equiv), and Pd(PPh₃)₄ (1.44 g, 1.25 mmol, 0.26 equiv). The mixture wasstirred for 2 h at 100° C. The reaction was cooled to room temperature,filtered, and the filtrate was concentrated under reduced pressure. Thecrude product was used to the next step directly without furtherpurification. LCMS (ES) [M+1]⁺ m/z: 372.

Step 4

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed5-[2-(oxan-2-yloxy)ethyl]-2-(trimethylstannyl)pyridine (1.50 g, 4.05mmol, 1.0 equiv), dioxane (20.0 mL),N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(Intermediate II, 700 mg, 2.36 mmol, 0.58 equiv), and Pd(PPh₃)₄ (932.00mg, 0.81 mmol, 0.20 equiv). The mixture was stirred for 12 h at 100° C.The mixture was concentrated to remove the solvent, and the residue waspurified by silica gel column with THF/petroleum ether (70%). Thisresulted in 184 mg (9.7%) ofN-(tert-butyl)-2-(methyl(2-(5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamideas yellow oil. LCMS (ES) [M+1]⁺ m/z: 468.

Step 5

Into a 20-mL vial, was placedN-tert-butyl-2-[methyl(2-[5-[2-(oxan-2-yloxy)ethyl]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(184 mg, 0.39 mmol, 1.0 equiv), methanol (5.0 mL), and TsOH (68 mg, 0.40mmol, 1.0 equiv). The mixture was stirred for 1 h at room temperature.The crude product was purified by Prep-HPLC with the followingconditions: Column, Atlantis HILIC OBD Column, 19*150 mm*5 um, mobilephase, Water (10 mmol/L NH₄HCO₃) and MeOH:CH₃CN=1:1 (33% Phase B up to45% within 9 min); Detector, UV 254 nm. This resulted in 89.2 mg (59%)ofN-(tert-butyl)-2-((2-(5-(2-hydroxyethyl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas an off-white solid. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 8.51 (d, J=1.8Hz, 1H), 8.25 (d, J=8.1 Hz, 1H), 7.72 (dd, J=8.1, 2.1 Hz, 1H), 7.68 (s,1H), 4.72 (t, J=5.1 Hz, 1H), 4.13 (s, 2H), 3.70-3.63 (m, 2H), 3.26 (s,3H), 3.14 (t, J=7.2 Hz, 2H), 2.84-2.78 (m, 4H), 2.04-1.96 (m, 2H), 1.25(s, 9H). LCMS: (ES, m/z): [M+H]⁺: 384.2.

Example 1.75 Synthesis ofN-tert-butyl-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 44)

Scheme 46a depicts a synthetic route for preparing an exemplarycompound.

Step 1

Into a 50-mL round-bottom flask was placed a mixture of2-chloropyridin-4-ol (2.00 g, 15.439 mmol, 1.00 equiv), DMF (20 ml),K₂CO₃ (4.27 g, 30.878 mmol, 2.00 equiv), and 2-(2-bromoethoxy)oxane(4.84 g, 23.159 mmol, 1.50 equiv). The resulting solution was stirredfor 16 hours at 70° C. The resulting solution was diluted with 100 mL ofH₂O. The resulting solution was extracted with 3×100 mL of ethylacetate. The organic layers were combined, washed with 100 ml of brine,dried over anhydrous sodium sulfate, and concentrated. This resulted in2.15 g (54.04%) of 2-chloro-4-[2-(oxan-2-yloxy)ethoxy]pyridine as alight yellow oil. LCMS (ES) [M+1]⁺ m/z: 258.

Step 2

Into a 40-mL vial, was placed a mixture of2-chloro-4-[2-(oxan-2-yloxy)ethoxy]pyridine (1.00 g, 3.88 mmol, 1.00equiv), dioxane (10.0 mL), hexamethyldistannane (1.91 g, 5.82 mmol, 1.50equiv), and Pd(PPh₃)₄ (896 mg, 0.776 mmol, 0.20 equiv). The resultingsolution was stirred for 2 hours at 100° C. The resulting mixture wasconcentrated. This resulted product was used directly in the next step.LCMS (ES) [M+1]⁺ m/z: 388.

Step 3

Into a 40-mL vial, was placed a mixture of4-[2-(oxan-2-yloxy)ethoxy]-2-(trimethylstannyl)pyridine (800 mg, 2.07mmol, 1.00 equiv), dioxane (10.00 mL),N-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(Intermediate II, 430 mg, 1.45 mmol, 0.70 equiv), and Pd(PPh₃)₄ (478 mg,0.414 mmol, 0.20 equiv). The resulting solution was stirred for 16 hoursat 100° C. The crude reaction mixture was filtered and subjected toreverse phase preparative MPLC (Prep-C18, 20-45 mM, 120 g, TianjinBonna-Agela Technologies; gradient elution of 10% MeCN in water to 48%MeCN in water over a 15 min period, where both solvents contain 0.1%NH₄HCO₃). The resulting mixture was concentrated. This resulted in 280mg (27.94%) ofN-(tert-butyl)-2-(methyl(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamideas a off-white solid. LCMS (ES) [M+1]⁺ m/z: 484.

Step 4

Into a 40-mL vial was placed a mixture ofN-(tert-butyl)-2-(methyl(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide(250 mg, 0.517 mmol, 1.00 equiv), MeOH (10.0 mL) and TsOH (89 mg, 0.52mmol, 1.0 equiv). The resulting solution was stirred for 2 hours at roomtemperature. The resulting mixture was concentrated. The crude productwas purified by Prep-HPLC with the following conditions: Column, XbridgePrep C18 OBD Column, 19×150 mm, 5 um; mobile phase, phase A: H₂O (0.05%NH₃H₂O); phase B: CH₃CN (20% CH₃CN up to 70% CH₃CN in 13 min). Thisresulted in 72.6 mg (35.15%) ofN-(tert-butyl)-2-((2-(4-(2-hydroxyethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 8.47 (d, J=5.6 Hz,1H), 7.85 (d, J=2.5 Hz, 1H), 7.68 (s, 1H), 7.04 (dd, J=5.7, 2.6 Hz, 1H),4.92 (t, J=5.4 Hz, 1H), 4.19-4.10 (m, 4H), 3.76 (q, J=5.1 Hz, 2H), 3.26(s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.01-1.96 (m,2H), 1.24 (s, 9H). LCMS (ES) [M+1]⁺ m/z: 400.2.

Scheme 46b depicts a synthetic route for preparing an exemplarycompound.

Step 1

Into a 50-mL 3-necked round-bottom flask was placedN-(tert-butoxycarbonyl)-N-methylglycine (20.0 g, 0.105 mol, 1.00 equiv),DMF (200.00 mL), 2-methylpropan-2-amine (8.43 g, 0.115 mol, 1.10 equiv)and DIEA (27.21 g, 0.211 mmol, 2.00 equiv). This was followed by theaddition of HATU (44.08 g, 0.115 mol, 1.10 equiv) in several batches at0° C. After addition, the resulting solution was stirred for 16 h atroom temperature. The reaction was quenched with 200 mL of water,extracted with 3×100 mL of ethyl acetate. The combined organic phase waswashed with 2×200 mL of water and 1×200 mL brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated under reducedpressure, the residue was purified by silica gel column with ethylacetate/petroleum ether (1:1) to give 20.6 g (80%) of tert-butyl(2-(tert-butylamino)-2-oxoethyl)(methyl)carbamate as an off white solid.LCMS (ES) [M+1]⁺ m/z: 245.

Step 2

Into a 500-mL 3-round-bottom flask was placed tert-butyl(2-(tert-butylamino)-2-oxoethyl)(methyl)carbamate (25 g, 102.4 mmol,1.00 equiv) and DCM (100.00 mL). This was followed by the addition ofHCl (g) (4 M in dioxane) (200.00 mL) dropwise with stirring at 0° C. Theresulting solution was stirred for 16 h at room temperature,concentrated in vacuum to remove the solvent and washed with ethylacetate (150 mL). This resulted in 16 g (86%) ofN-(tert-butyl)-2-(methylamino)acetamide hydrochloride. LCMS (ES)[M−HCl+1]⁺ m/z: 145.

Step 3

Into a 500-mL 3 neck round-bottom flask was placedN-(tert-butyl)-2-(methylamino)acetamide hydrochloride (16 g, 88.9 mmol,1.00 equiv), NMP (200.00 mL),2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (16.8 g, 88.9 mmol,1.00 equiv) and DIEA (40.6 g, 0.315 mol, 3.00 equiv). The resultingsolution was stirred for 6 h at 50° C. in oil bath. The reaction mixturewas cooled to room temperature, diluted with 200 mL of water andextracted with 3×200 mL of ethyl acetate. The combined organic phase waswashed with 3×300 mL of water and brine 1×200 mL, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated under reducedpressure, the residue was triturated with ethyl acetate and filtered.This resulted in 18.4 g (70%) ofN-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a white solid. LCMS (ES) [M+1]⁺ m/z: 297.

Step 4

4-fluoro-2-(tributylstannyl)pyridine was synthesized as following: To asolution of 2-bromo-4-fluoropyridine (25 g, 142 mmol, 1.00 eq.) inToluene (300 mL) was added butyllithium (62.5 mL, 2.50 mol/L, 156 mmol,1.10 eq.) at −78° C., after stirred for 1 h, the mixture was addedtributyl(chloro)stannane (50.7 g, 156 mmol, 1.10 eq.) and was furtherstirred for 30 min at −78° C. and 3 h. at room temperature The mixturewas quenched with ice water, extracted with hexane, organic layers werecombined and washed with Sat. NaHCO₃, brine, dried and filtered. Thefiltrate was concentrated to give crude product (51 g) as clear yellowoil, which was used without purification. LCMS (ES) [M+1]⁺ m/z: 388.

Into a 250-mL three necked round bottom flask purged and maintained withan inert atmosphere of nitrogen was placedN-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(10 g, 33.8 mmol, 1.00 equiv), toluene (150.00 mL),4-fluoro-2-(tributylstannyl)pyridine (21.7 g, 60.84 mmol, 1.8 equiv) andPd(PPh₃)₄ (3.57 g, 3.38 mmol, 0.10 equiv). The mixture was stirred for60 h at 110° C. in oil bath. The reaction mixture was cooled to roomtemperature, concentrated to remove the solvent; the residue waspurified by silica gel column with dichloromethane/methanol (10:1). Thisresulted in 7 g (58%) ofN-(tert-butyl)-2-((2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas yellow solid. LCMS (ES) [M+1]⁺ m/z: 358.

Step 5

Into a 250 mL 3-neck flask was placed ethane-1,2-diol (9.55 g, 154 mmol,10.0 equiv) and DMF (100 mL), NaH (60% in mineral oil) (6.16 g, 154mmol, 10.0 equiv) was added in portion wise at 0-5° C. The mixture wasstirred for 1 h at room temperature andN-(tert-butyl)-2-((2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(5.5 g, 15.4 mmol, 1.00 equiv) was added at 0-5° C. The reaction mixturewas stirred for 5 h at 50° C. (The reaction was repeated in 2 batches).The reaction mixture was cooled to room temperature, diluted with 200 mLof water, extracted with 3×200 mL of ethyl acetate. The combined organicphase was washed with 3×300 ml of water and brine 1×200 mL, dried overanhydrous sodium sulfate. The residue was purified by Prep-HPLC withconditions: column, C18-800 g, Mobile phase, CH₃CN/H₂O (0.05% FA), from10% increased to 70% within 27 min, Flow rate, 180 mL/min, Detector, 254nm. The pH value of the fraction was adjusted to 7˜8 with K₂CO₃ solid,extracted with dichloromethane (3×300 mL). The combined organic phasewas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure and the residue was freezing dried,this resulted in 5.03 g (41%) ofN-(tert-butyl)-2-((2-(4-(2-hydroxyethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a white solid. LCMS: (ES, m/z): [M+H]⁺: 400. ¹H-NMR: (300 MHz,DMSO-d6, ppm): δ 8.47 (d, J=5.6 Hz, 1H), 7.86 (d, J=2.5 Hz, 1H), 7.68(s, 1H), 7.04 (dd, J=5.6, 2.6 Hz, 1H), 4.92 (t, J=5.4 Hz, 1H), 4.19-4.10(m, 4H), 3.77 (q, J=5.1 Hz, 2H), 3.26 (s, 3H), 3.13 (t, J=7.3 Hz, 2H),2.81 (t, J=7.9 Hz, 2H), 2.01-1.96 (m, 2H), 1.24 (s, 9H).

Synthesis of Compound 44—Route 2

Into a 250-mL round-bottom flask were placedN-tert-butyl-2-[[2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamide(7.40 g, 19.79 mmol, 1.00 equiv), 2-(oxan-2-yloxy)ethanol (4.34 g, 29.69mmol, 1.50 equiv), DMF (150.00 mL) and t-BuOK (6.66 g, 59.37 mmol, 3.00equiv). The resulting solution was stirred for overnight at 25° C. Thereaction was then quenched by the addition of water/ice. The resultingsolution was extracted with 3×200 mL of ethyl acetate and the organiclayers combined, dried over anhydrous sodium sulfate and concentrated.The crude product (8 g) was purified by Prep-HPLC with the followingconditions: Column, XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um;mobile phase, Water (0.1% NH₃·H₂O) and CAN (20% Phase B up to 60% in 11min); Detector, 254. This resulted in 6 g (62.69%) ofN-tert-butyl-2-[methyl(2-[4-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamideas yellow solid. LCMS (ES) [M+1]⁺ m/z: 484.

Into a 40-mL vial were placed N-tert-butyl-2-[methyl(2-[4-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(1.00 g, 2.07 mmol, 1.00 equiv), MeOH (10.00 mL) and HCl (6M) (1.00 mL).The resulting solution was stirred for 1 h at room temperature. Thecrude product (1 g) was purified by Prep-HPLC with the followingconditions: Column, XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um;mobile phase, Water (0.1% NH₃·H₂O) and ACN (15% Phase B up to 60% in 11min); Detector, 254 nm. This resulted in 613.5 mg (74.27%) ofN-tert-butyl-2-([2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamideas white solid. LCMS (ES, m/z): [M+H]⁺: 400. ¹H-NMR (300 MHz, DMSO-d₆,ppm): δ 8.47 (d, J=5.6 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.68 (s, 1H),7.04 (dd, J=5.7, 2.6 Hz, 1H), 4.92 (t, J=5.4 Hz, 1H), 4.21-4.07 (m, 4H),3.76 (q, J=5.1 Hz, 2H), 3.26 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.81 (t,J=7.8 Hz, 2H), 2.01-1.96 (m, 2H), 1.24 (s, 9H).

Example 1.76 Synthesis of4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepan-2-one(Compound 47)

Compound 47 was synthesized similar to compound 92 by replacing azapanewith 1,4-diazepan-2-one. LCMS (ES+): (M+H)⁺=310.0. ¹H NMR (400 MHz,DMSO-d6) δ 8.82-8.76 (m, 1H), 8.52 (d, J=7.9 Hz, 1H), 8.12-8.05 (m, 1H),7.70-7.61 (m, 2H), 6.52 (s, 1H), 4.48 (s, 2H), 4.16-4.06 (m, 2H),3.27-3.22 (m, 4H), 2.99 (t, J=7.9 Hz, 2H), 2.14-2.03 (m, 2H), 1.92-1.83(m, 2H).

Example 1.77 Synthesis of1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepan-5-one(Compound 50)

Compound 50 was synthesized similar to compound 92 by replacing azapanewith 1,4-diazepan-5-one. LCMS (ES+): (M+H)⁺=309.9. ¹H NMR (400 MHz,DMSO-d6) δ 8.76-8.69 (m, 1H), 8.34 (d, J=7.9 Hz, 1H), 8.01-7.92 (m, 1H),7.73-7.64 (m, 1H), 7.57-7.48 (m, 1H), 3.98-3.92 (m, 4H), 3.29-3.26 (m,2H), 3.10-3.03 (m, 2H), 2.93-2.87 (m, 2H), 2.65-2.60 (m, 2H), 2.09-2.00(m, 2H).

Example 1.78 Synthesis of(2R)—N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 51)

Scheme 47 depicts a synthetic route for preparing an exemplary compound.

Step 1

2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (130.00 mg; 0.69mmol; 1.00 eq.) was dissolved in acetonitrile (2.5 ml), and to thesolution was added methyl (2R)-2-(methylamino)propanoate hydrochloride(126.76 mg; 0.83 mmol; 1.20 eq.) and Hunig's base (0.48 mL; 2.75 mmol;4.00 eq.). After being stirred at ˜55° C. for 15 h, the mixture wasevaporated and the residue was subjected to column chromatography togive methyl(2R)-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)propanoate(54 mg, 31%) as a film. LCMS (ES+): (M+H)⁺=270.2.

Methyl(2R)-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)propanoate(54 mg; 0.20 mmol; 1 eq.) was dissolved in THF (2 ml) and methanol (0.5ml). Lithium hydroxide (anhydrous, 19 mg; 0.8 mmol; 4 eq.) dissolved in˜0.8 ml of water was added dropwise and the reaction was stirred at 25°C. for 1.5 h. 6 M HCl was added carefully to acidify the reaction topH<3. The solvents were evaporated and the residue was dried on highvacuum. The residue of(2R)-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)propanoicacid (51 mg; 0.2 mmol; 1 eq.) was dissolved in N,N-dimethylformamide (2ml). N, N-diisopropylethylamine (0.12 mL; 0.7 mmol; 3.5 eq.) was addedand the reaction was stirred in an ice bath. Tert-butylamine (32 μL; 0.3mmol; 1.5 eq.) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, (152 mg; 0.4 mmol; 2 eq.) were added.After 4 h, ethyl acetate (50 ml), water (10 ml), and sodium bicarbonatesolution (10 ml) were added. The phases were separated, and the aqueousphase was extracted with ethyl acetate (50 ml). The organic phases werewashed with water (10 ml) and sodium chloride solution (20 ml), anddried over sodium sulfate. After evaporation, the product was purifiedby silica gel chromatography (ethyl acetate/hexanes gradient) to give(2R)—N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)propenamide(12.5 mg, 20%). MS (ES+): (M+H)⁺=310.9.

Step 3

(2R)—N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)propanamide(30.00 mg; 0.10 mmol; 1.00 eq.) was dissolved in 1,4-dioxane (1 ml) andthe solution was purged with Ar gas. 2-(tributylstannyl)pyridine (0.06mL; 0.19 mmol; 2.00 eq.) and tetrakis(triphenylphosphane) palladium(11.15 mg; 0.01 mmol; 0.10 eq.) were added The reaction vessel wassealed and stirred in a heat bath at 110° C. for 15 h. Afterevaporation, the residue was purified by reverse phase chromatography(Waters XSelect CSH C18 column, 0-70% acetonitrile/0.1% aqueous formicacid gradient) to give(2R)—N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(11 mg, 32%) as an off-white solid. LCMS (ES+): (M+H)⁺=354.4. ¹H NMR(400 MHz, Methanol-d4) δ 8.72 (ddd, J=4.9, 1.8, 0.9 Hz, 1H), 8.46-8.41(m, 1H), 8.02-7.95 (m, 1H), 7.68 (s, 1H), 7.57-7.50 (m, 1H), 5.26 (q,J=7.1 Hz, 1H), 3.38-3.33 (m, 1H), 3.28-3.18 (m, 1H), 3.08-2.91 (m, 2H),2.24-2.06 (m, 2H), 1.48 (d, J=7.1 Hz, 3H), 1.25 (s, 9H).

Example 1.79 Synthesis of(2S)—N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 52)

Compound 52 was synthesized similar to compound 51 by replacing(2R)-2-(methylamino)propanoate with (2S)-2-(methylamino)propanoate. LCMS(ES+): (M+H)⁺=354.4. ¹H NMR (400 MHz, Methanol-d4) δ 8.72 (ddd, J=4.8,1.8, 0.9 Hz, 1H), 8.46-8.40 (m, 1H), 8.02-7.95 (m, 1H), 7.68 (s, 1H),7.54 (ddd, J=7.6, 4.8, 1.2 Hz, 1H), 5.26 (q, J=7.1 Hz, 1H), 3.38-3.32(m, 1H), 3.28-3.18 (m, 1H), 3.09-2.91 (m, 2H), 2.23-2.04 (m, 2H), 1.48(d, J=7.2 Hz, 3H), 1.25 (s, 9H).

Example 1.80 Synthesis of1-[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane(Compound 53)

Compound 53 was synthesized similar to Compound 92 by replacing(2-tributylstannyl)pyridine with 4-methoxy-2-(tributylstannyl)pyridine.¹H NMR (400 MHz, Methanol-d₄) δ 8.48 (d, J=5.8 Hz, 1H), 7.86 (d, J=2.6Hz, 1H), 7.06 (dd, J=5.8, 2.6 Hz, 1H), 3.94 (s, 3H), 3.86 (t, J=6.1 Hz,4H), 3.15 (t, J=7.3 Hz, 2H), 2.92 (t, J=7.9 Hz, 2H), 2.16-2.04 (m, 2H),1.83 (q, J=5.5 Hz, 4H), 1.59 (p, J=2.7 Hz, 4H). LCMS (ES+):(M+H)⁺=325.1.

Example 1.81 Synthesis of(3R)-6,6-dimethyl-3-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}piperidin-2-one(Compound 55)

Scheme 48 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 100-mL 3-necked round-bottom flask, Zn (2.98 g, 45.6 mmol, 3.0equiv) was suspended in dry (DMF) (30 mL) under nitrogen atmosphere, andiodine (two crystals) was added immediately. A change in color fromcolorless to dark brown and colorless again was observed. Methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (5.0 g, 15.2 mmol,1.0 equiv), was added followed immediately by iodine (three crystals),the aforementioned color change was observed once more, and theinsertion process was allowed to proceed for 2 h. A flask containingCuBr-Me₂S (0.31 g, 1.53 mmol, 0.1 equiv), was placed under vacuum andheated vigorously until the gray CuBr-Me₂S became light green/yellow.The flask was then placed under a flow of nitrogen and allowed to coolto room temperature. This was repeated once more, and the flask wasallowed to cool to room temperature. A prepared solution of Zn Reagentin DMF was transferred to the flask containing CuBr-Me₂S (2.06 g, 22.78mmol, 2.0 equiv), and the reaction was stirred for 72 h at roomtemperature. The reaction mixture was then filtered through a silicaplug eluting with EtOAc. The organic phase was washed with water (2×50mL) and brine (50 mL). The organic phase was dried with Na₂SO₄,filtered, and the solvent removed under reduced pressure. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1:50 to 1:1). This resulted in 3 g (76.7%) of methyl(2R)-2-[(tert-butoxycarbonyl)amino]-5-methylhex-5-enoate as an oil. LCMS(ES) [M+1]⁺ m/z: 258.2.

Step 2

Into a 500-mL 3-necked round-bottom flask, Fe₂ (OX)₃·6H₂O (3.76 g, 7.77mmol, 2.0 equiv) was stirred in H₂O (150 mL) until completely dissolved(typically 2 h). The clear yellow solution was cooled to 0° C. anddegassed with Ar for 10 min. NaN₃ (0.76 g, 11.66 mmol, 3.0 equiv) andethanol (75 mL) were added. After 20 min, a solution of methyl(2R)-2-[(tert-butoxycarbonyl)amino]-5-methylhex-5-enoate (1.00 g, 3.886mmol, 1.00 equiv) in EtOH (75 mL) was added to the reaction mixture,followed by NaBH₄ (1.03 g, 27.202 mmol, 7 equiv) at 0° C. The resultingmixture was stirred for 30 min before being quenched by the addition of30% aqueous NH₄OH (4 mL). The mixture was extracted with 10% MeOH inCH₂Cl₂, the organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by flash chromatography (SiO₂, 20% EtOAc/PE) togive methyl(2R)-5-azido-2-[(tert-butoxycarbonyl)amino]-5-methylhexanoate (450 mg,38.5%) as a colorless oil. LCMS (ES) [M+1]⁺ m/z: 301.2.

Step 3

To a solution of methyl(2R)-5-azido-2-[(tert-butoxycarbonyl)amino]-5-methylhexanoate (450 mg,1.50 mmol, 1.0 equiv) in EtOAc (15 mL) was added Pd/C (200 mg) at roomtemperature. After the addition, the reaction was purged with H₂ threetimes. The resulting mixture was stirred for 16 hr at 25° C. under a H₂atmosphere. The resulting mixture was filtered, and the filtrate wasconcentrated to give 220 mg (60.6%) of tert-butylN-[(3R)-6,6-dimethyl-2-oxopiperidin-3-yl]carbamate as an off whitesolid. LCMS (ES) [M+1]⁺ m/z: 243.3.

Step 4

Into a 100-mL round-bottom flask, was placed tert-butylN-[(3R)-6,6-dimethyl-2-oxopiperidin-3-yl]carbamate (220 mg, 0.91 mmol,1.0 equiv), EtOAc (5 mL), and HCl/EtOAc (2 mL, 2 M, 4.0 mmol, 4.4equiv). The resulting solution was stirred for 5 h at 25° C. Theresulting mixture was concentrated under vacuum. This resulted in 150 mg(100%) of (3R)-3-amino-6,6-dimethylpiperidin-2-one as an off whitesolid. LCMS (ES) [M+1]⁺ m/z: 143.

Step 5

Into a 50-mL round-bottom flask, was placed(3R)-3-amino-6,6-dimethylpiperidin-2-one (150 mg, 1.05 mmol, 1.0 equiv),2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (199 mg, 1.05 mmol, 1.0equiv), NMP (5 mL), and DIPEA (409 mg, 3.16 mmol, 3.0 equiv). Theresulting solution was stirred for 16 h at 60° C. in an oil bath. Thereaction mixture was cooled to room temperature. The reaction was thenquenched by the addition of 20 mL of water. The resulting solution wasextracted with 3×30 mL of ethyl acetate, dried over anhydrous sodiumsulfate, and concentrated. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:50 to 1:1). This resultedin 160 mg (51.5%) of(3R)-3-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino)-6,6-dimethylpiperidin-2-oneas a white solid. LCMS (ES) [M+1]⁺ m/z: 295.2.

Step 6

To a solution of(3R)-3-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino)-6,6-dimethylpiperidin-2-one(160 mg, 0.54 mmol, 1.0 equiv) and 2-(tributylstannyl)pyridine (200 mg,0.54 mmol, 1.0 equiv) in dioxane (5 mL) was added Pd(PPh₃)₄ (62 mg, 0.05mmol, 0.1 equiv) at 25° C. in one portion. After the addition, theresulting solution was stirred for 16 hr at 100° C. under an Aratmosphere. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:50 to 10:1). The crude product (150 mg) waspurified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, C18 silica gel; mobile phase, MeCN=10/90increasing to MeCN=90/10 within 15 min; Detector, 220. This resulted in57.5 mg (31.4%) of(3R)-6,6-dimethyl-3-[[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]piperidin-2-oneas a white solid. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 8.65 (d, J=3.9 Hz,1H), 8.23 (d, J=7.8 Hz, 1H), 7.89 (dd, J=1.5 Hz, 7.5 Hz, 1H), 7.57 (s,1H), 7.44 (dd, J=1.2 Hz, 6.0 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.67-4.52(m, 1H), 2.84 (t, J=7.5 Hz, 2H), 2.72 (t, J=7.2 Hz, 2H), 2.12-1.96 (m,4H), 1.78-1.76 (m, 2H), 1.23 (d, J=10.8 Hz, 6H). LCMS (ES) [M+1]⁺ m/z:338.2.

Example 1.82 Synthesis of(3S)-6,6-dimethyl-3-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}piperidin-2-one(Compound 56)

Compound 56 was synthesized similar to Compound 55 by replacing Methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate with Methyl(2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate. ¹H NMR (300 MHz,DMSO-d₆, ppm) δ 8.65 (d, J=3.6 Hz, 1H), 8.23 (d, J=7.8 Hz, 1H), 7.89(dd, J=1.8 Hz, 7.8 Hz, 1H), 7.57 (s, 1H), 7.44 (dd, J=0.9 Hz, 4.8 Hz,1H), 7.06 (d, J=8.1 Hz, 1H), 4.71-4.53 (m, 1H), 2.84 (t, J=8.1 Hz, 2H),2.72 (t, J=7.2 Hz, 2H), 2.15-1.95 (m, 4H), 1.79-1.76 (m, 2H), 1.25 (d,J=10.8 Hz, 6H). LCMS (ES) [M+1]⁺ m/z: 338.2.

Example 1.83 Synthesis ofN-tert-butyl-2-{[2-(4-cyclopropylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 57)

Scheme 49 depicts a synthetic route for preparing an exemplary compound.

Step 1

To a mixture of 2-chloro-4-methoxypyridine (1.0 g, 6.32 mmol, 1.00equiv), cyclopropylboronic acid (0.68 g, 6.9 mmol, 1.25 equiv) andNa₂CO₃ (1.68 g, 15.8 mmol, 2.50 equiv) in dioxane (20 mL)/H₂O (1 mL) wasadded Pd(dppf)Cl₂·CH₂Cl₂ (50 mg, 0.064 mmol, 0.01 equiv) at roomtemperature. The resulting mixture was stirred for 16 h at 80° C. in anoil bath under an Ar atmosphere. The resulting mixture was concentrated.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:100 to 1:10). This resulted in 500 mg(66.29%) of 4-cyclopropylpyridine as a solid. LCMS (ES) [M+1]⁺ m/z:120.1. ¹H NMR (300 MHz, CDCl3, ppm) δ 8.45 (d, J=5.1 Hz, 2H), 6.98 (dd,J=4.5, 1.5 Hz, 2H), 1.92-1.84 (m, 1H), 1.28-1.10 (m, 2H), 0.84-0.81 (m,2H).

Step 2

To a mixture of 2-(dimethylamino)ethan-1-ol (523 mg, 5.87 mmol, 2.0equiv) in hexane (20 mL), was added n-BuLi (2.3 mL, 2.5 M, 5.87 mmol,2.0 equiv) at −78° C. under a N₂ atmosphere. After the reaction wasstirred at −78° C. for 20 min, Bu₃SnCl (1.9 g, 5.8 mmol, 2.0 equiv) and4-cyclopropylpyridine (350 mg, 2.94 mmol, 1.0 equiv) were added. Theresulting mixture was stirred for 2 h between −78° C. to roomtemperature. The reaction was then quenched by the addition of water.The resulting solution was extracted with 3×50 mL of ethyl acetate, theorganic layers were combined, dried over Na₂SO₄, and concentrated undervacuum to give 600 mg of the crude4-cyclopropyl-2-(tributylstannyl)pyridine as a yellow gum. LCMS (ES)[M+1]⁺ m/z: 410.1.

Step 3

Into a 50-mL 3-necked round-bottom flask purged and maintained in aninert atmosphere of argon was placed4-cyclopropyl-2-(tributylstannyl)pyridine (200 mg, 0.49 mmol, 1.00equiv),N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(Intermediate II, 72.7 mg, 0.25 mmol, 0.5 equiv), Pd(PPh₃)₄ (56.6 mg,0.05 mmol, 0.1 equiv) and dioxane (5 mL). The resulting solution wasstirred for 16 hr at 100° C. The resulting mixture was concentrated. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:10 to 10:1). The crude product (150 mg) waspurified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, C18; mobile phase, Mobile phase: MeCN=5/1B:Water Flow rate: 20 mL/min Column: DAICEL CHIRALPAK IC, 250*20 mm, 220nm Gradient: 50% B in 20 min; 220 nm; This resulted in 87.6 mg (47.11%)ofN-tert-butyl-2-[[2-(4-cyclopropylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.47 (d, J=5.1 Hz, 1H),8.16 (s, 1H), 8.08 (d, J=1.8 Hz, 1H), 7.68 (s, 1H), 7.06 (dd, J=5.1, 1.8Hz, Hz, 1H), 4.15 (s, 2H), 3.50 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.82(t, J=7.8 Hz, 2H), 2.28-1.97 (m, 3H), 1.23 (s, 9H), 1.13-1.07 (m, 2H),0.88-0.82 (m, 2H). LCMS (ES) [M+1]⁺ m/z: 380.2.

Example 1.84 Synthesis ofN-tert-butyl-2-{[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 58)

Scheme 50 depicts a synthetic route for preparing an exemplary compound.

Into a 50-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed 4-fluoro-2-(trimethylstannyl)pyridine(1.00 g, 3.85 mmol, 1.00 equiv),N-tert-butyl-2-[5H,6H,7H-cyclopenta[d]pyrimidin-4-yl(methyl)amino]acetamide(Intermediate II, 500 mg, 1.91 mmol, 0.50 equiv), Pd(dppf)Cl₂ (350 mg,0.43 mmol, 0.10 equiv), and dioxane (20.0 mL). The mixture was stirredfor 12 h at 100° C. The mixture was concentrated to remove the solvent,the resulting residue was purified by silica gel column with THF/PE(70%) and the collected product was further purified by Prep-HPLC withconditions: Column, Welch Xtimate C18, 21.2*250 mm, 5 um, mobile phase,Water (10 mmol/L NH₄HCO₃) and MeOH:CH₃CN=1:1 (25% Phase B up to 65% in15 min), Detector, UV, 254 nm. This resulted in 42.9 mg (3%) ofN-(tert-butyl)-2-((2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a white solid. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 8.69 (dd, J=9.0, 5.4Hz, 1H), 8.16 (dd, J=10.8, 2.7 Hz, 1H), 7.73 (s, 1H), 7.42-7.37 (m, 1H),4.12 (s, 2H), 3.30 (s, 3H), 3.17 (t, J=7.2 Hz, 2H), 2.82 (t, J=7.8 Hz,2H), 2.05-1.95 (m, 2H), 1.24 (s, 9H).

LCMS (ES, m/z): [M+H]⁺: 358.1.

Example 1.85 Synthesis of-tert-butyl-2-{methyl[2-(6-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 59)

Scheme 51 depicts a synthetic route for preparing an exemplary compound.

To a solution ofN-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(Intermediate II, 200.00 mg, 0.674 mmol, 1.00 equiv) and2-methyl-6-(tributylstannyl)pyridine (386.30 mg, 1.011 mmol, 1.5 equiv)in dioxane (4 ml) was added Pd(dppf)Cl₂ (49.31 mg, 0.067 mmol, 0.10equiv). After stirring for 4 h at 100° C. under a nitrogen atmosphere,the resulting mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography and eluted withPE/THF (1:5) to affordN-tert-butyl-2-[methyl[2-(6-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide(125 mg, 52.48%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) 1H NMR (300MHz, DMSO-d6) δ 8.15 (d, J=7.8 Hz, 1H), 7.75 (t, J=7.7 Hz, 1H), 7.66 (s,1H), 7.29 (d, J=7.6 Hz, 1H), 4.13 (s, 2H), 3.27 (s, 3H), 3.14 (t, J=7.4Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.55 (s, 3H), 2.14-1.83 (m, 2H), 1.24(s, 9H). LCMS (ES) [M+1]⁺ m/z: 354.3.

Example 1.86 Synthesis ofN-tert-butyl-2-{[2-(4,5-dimethylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 60)

Scheme 52 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 250-mL 3-necked round-bottom flask purged and maintained in aninert atmosphere of nitrogen was placed 3,4-dimethylpyridine (1.00 g,9.332 mmol, 1.00 equiv) and THE (20.00 mL). The mixture was stirred at0° C., then butyllithium (1.76 mL, 27.448 mmol, 2 equiv) was addeddropwise. The resulting solution was stirred at 0° C. for 1 hr anddimethylaminoethanol (1.25 g, 14.023 mmol, 1.50 equiv) was addeddropwise. The resulting solution was stirred for an additional 1 hr at0° C., cooled down to −78° C. and tributyltin chloride (4.56 g, 13.998mmol, 1.5 equiv) was added dropwise. The resulting solution was stirredfor an additional 1 h at −78° C. The reaction was then quenched by theaddition of water. The resulting mixture was extracted with 3×30 mL ofethyl acetate and the organic layers were combined and dried overanhydrous sodium sulfate and concentrated under vacuum. This resulted in400 mg (10.82%) of 4,5-dimethyl-2-(tributylstannyl)pyridine as a solid.LCMS (ES) [M+1]⁺ m/z: 398.

Step 2

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed4,5-dimethyl-2-(tributylstannyl)pyridine (400.48 mg, 1.011 mmol, 1.20equiv),N-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(Intermediate II, 250.00 mg, 0.842 mmol, 1.00 equiv), Pd(PPh₃)₄ (97.33mg, 0.084 mmol, 0.10 equiv), LiCl (35.71 mg, 0.842 mmol, 1.00 equiv),and Toluene (10.00 mL). The resulting solution was stirred for 16 hr at100° C. The reaction mixture was cooled and concentrated. The residuewas applied onto a silica gel column and eluted withdichloromethane/methanol (10:1). The collected crude product was furtherpurified by Prep-HPLC with the following conditions (2 #SHIMADZU(HPLC-01)): Column, Welch Xtimate C18, 21.2*250 mm, 5 um; mobile phase,Water (0.05% TFA) and MeOH:ACN=1:1 (10% PhaseB up to 60% in 17 min. Thisresulted in 68.3 mg (22.06%) ofN-(tert-butyl)-2-((2-(4,5-dimethylpyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.37 (s, 1H), 8.14 (s,1H), 7.72 (s, 1H), 4.14 (s, 2H), 3.27 (s, 3H), 3.14 (t, J=7.3 Hz, 2H),2.80 (t, J=7.8 Hz, 2H), 2.34 (s, 3H), 2.27 (s, 3H), 2.03-1.92 (m, 2H),1.24 (s, 9H). LCMS (ES) [M+1]⁺ m/z: 368.2

Example 1.87 Synthesis ofN-(1-hydroxy-2-methylpropan-2-yl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 61)

Scheme 53 depicts a synthetic route for preparing an exemplary compound.

Into a 20-mL vial was placed[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]aceticacid (Intermediate I, 200 mg, 0.70 mmol, 1.0 equiv), DMF (3.0 mL),2-amino-2-methyl-1-propanol (69 mg, 0.77 mmol, 1.1 equiv), and DIEA (455mg, 3.52 mmol, 5.0 equiv). This was followed by the addition of HATU(401 mg, 1.06 mmol, 1.5 equiv) at 0° C. The reaction solution wasstirred for 1 h at room temperature. The reaction solution was directlypurified by C18-120 g column eluted with CH₃CN/H₂O (1% NH₄OH), from 5%to 80% within 12 min, flow rate, 70 mL/min, detector, 254 nm. Thisresulted in 93.9 mg (38%) ofN-(1-hydroxy-2-methylpropan-2-yl)-2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamideas white solid. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 8.66 (dd, J=4.7, 1.8Hz, 1H), 8.33 (dt, J=8.0, 1.1 Hz, 1H), 7.88 (td, J=7.7, 1.8 Hz, 1H),7.51 (s, 1H), 7.44 (ddd, J=7.5, 4.8, 1.2 Hz, 1H), 4.82 (t, J=6.0 Hz,1H), 4.16 (s, 2H), 3.37 (d, J=5.7 Hz, 2H), 3.27 (s, 3H), 3.15 (t, J=7.2Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.03-1.97 (m, 2H), 1.17 (s, 6H). LCMS(ES, m/z): [M+H]⁺: 356.2.

Example 1.88 Synthesis ofN-(1-hydroxy-2-methylpropan-2-yl)-2-{methyl[2-(4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 62)

Scheme 54 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 250-mL round-bottom flask, was placed2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (10.00 g, 52.899mmol, 1.00 equiv), NMP (100.00 mL), ethyl 2-(methylamino)acetatehydrochloride (8.13 g, 52.899 mmol, 1.00 equiv), and DIEA (13.67 g,105.798 mmol, 2.00 equiv). The resulting solution was stirred for 1 hrat 60° C. The mixture was poured into 200 mL of ethyl acetate. Theorganic layer was separated and washed with 3×100 ml of water. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column andeluted with ethyl acetate/petroleum ether (1:3). The collected fractionswere combined and concentrated. This resulted in 8.2 g (57.47%) of ethylN-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinateas a yellow solid. LCMS (ES) [M+1]⁺ m/z 270.

Step 2

Into a 250-mL round-bottom flask, was placed ethylN-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinate(8.00 g, 29.659 mmol, 1.00 equiv), dioxane (100.00 mL),4-methyl-2-(tributylstannyl)pyridine (13.60 g, 35.591 mmol, 1.20 equiv),and tetrakis(triphenylphosphine)palladium(0) (3.43 g, 2.966 mmol, 0.10equiv). The resulting solution was stirred for 16 hr at 110° C. Theresulting mixture was concentrated. The residue was applied onto asilica gel column and eluted with ethyl acetate/petroleum ether (1:3).The collected fractions were combined and concentrated. This resulted in7.5 g (77.5%) of ethylN-methyl-N-(2-(4-methylpyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycinateas a yellow solid. LCMS (ES) [M+1]⁺ m/z 327.

Step 3

Into a 250-mL round-bottom flask was placed ethylN-methyl-N-(2-(4-methylpyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycinate(3.80 g, 11.642 mmol, 1 equiv), tetrahydrofuran (30 mL), water (30 mL),and lithium hydroxide (0.56 g, 23.284 mmol, 2.00 equiv). The resultingsolution was stirred for 2 hr at 25° C. The resulting mixture wasconcentrated. The resulting solution was diluted with 50 mL of water.The pH value of the solution was adjusted to 4 with HCl (1 mol/L). Theprecipitated solids were collected by filtration. This resulted in 3.4 g(97.89%) ofN-methyl-N-(2-(4-methylpyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycineas an off-white solid. LCMS (ES) [M+1]⁺ m/z 299.

Step 4

Into a 50-mL round-bottom flask, was placedN-methyl-N-(2-(4-methylpyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycine(100.00 mg, 0.335 mmol, 1.00 equiv), dimethylformamide (4.00 mL),2-amino-2-methyl-1-propanol (29.88 mg, 0.335 mmol, 1.00 equiv), HATU(191.17 mg, 0.503 mmol, 1.50 equiv), and DIEA (129.96 mg, 1.006 mmol,3.00 equiv). The resulting solution was stirred for 2 hr at 25° C. Thecrude reaction mixture was filtered and subjected to reverse phasepreparative HPLC (Prep-C18, 20-45M, 120 g, Tianjin Bonna-AgelaTechnologies; gradient elution of 25% MeCN in water to 35% MeCN in waterover a 10 min period, water contains 0.1% NH₃H₂O) to provideN-(1-hydroxy-2-methylpropan-2-yl)-2-{methyl[2-(4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamideas a yellow solid (69.6 mg, 56.20%). ¹H NMR (300 MHz, DMSO-d6) δ 8.61(d, J=5.0 Hz, 1H), 8.28 (s, 1H), 7.72 (s, 1H), 7.46 (d, J=4.9 Hz, 1H),4.83 (s, 1H), 4.30 (s, 2H), 3.32 (s, 5H), 3.21 (t, J=7.4 Hz, 2H), 2.93(t, J=7.8 Hz, 2H), 2.47 (s, 3H), 2.11-1.97 (m, 2H), 1.17 (s, 6H). LCMS(ES) [M+1]⁺ m/z 370.1.

Example 1.89 Synthesis ofN-(4-hydroxy-2-methylbutan-2-yl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 63)

Scheme 55 depicts a synthetic route for preparing an exemplary compound.

Into a 20-mL vial was placed[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]aceticacid (150 mg, 0.53 mmol, 1.0 equiv), DMF (3.0 mL),3-amino-3-methylbutan-1-ol (60 mg, 0.58 mmol, 1.10 equiv), and DIEA (341mg, 2.64 mmol, 5.0 equiv). This was followed by the addition of HATU(301 mg, 0.79 mmol, 1.5 equiv) at 0° C. The reaction solution wasstirred for 1 h at room temperature. The reaction solution was purifiedby Prep-HPLC with conditions: C18-120 g column, CH₃CN/H₂O (0.5% NH₄OH)from 5% to 80% within 15 min, flow rate: 70 mL/min, detector, 254 nm.This resulted in 86.5 mg (44%) ofN-(4-hydroxy-2-methylbutan-2-yl)-2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamideas an off-white solid. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 8.67 (ddd,J=4.8, 1.8, 0.9 Hz, 1H), 8.32 (dt, J=7.9, 1.1 Hz, 1H), 7.88 (td, J=7.7,1.8 Hz, 1H), 7.69 (s, 1H), 7.44 (ddd, J=7.5, 4.8, 1.3 Hz, 1H), 4.40 (t,J=4.8 Hz, 1H), 4.14 (s, 2H), 3.47-3.41 (m, 2H), 3.26 (s, 3H), 3.14 (t,J=7.2 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.05-1.95 (m, 2H), 1.76 (t, J=6.9Hz, 2H), 1.23 (s, 6H). LCMS (ES, m/z): [M+H]⁺: 370.3.

Example 1.90 Synthesis ofN-cyclopentyl-2-{methyl[2-(4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 64)

Compound 64 was synthesized similar to compound 62 by replacing2-amino-2-methyl-1-propanol with cyclopentanamine. ¹H NMR (300 MHz,DMSO-d6) δ 8.51 (d, J=4.9 Hz, 1H), 8.16-8.07 (m, 2H), 7.31-7.23 (m, 1H),4.17 (s, 2H), 4.06-3.95 (m, 1H), 3.30-3.20 (m, 3H), 3.15 (t, J=7.3 Hz,2H), 2.82 (t, J=7.8 Hz, 2H), 2.40 (s, 3H), 2.03-1.93 (m, 2H), 1.85-1.68(m, 2H), 1.70-1.30 (m, 6H). LCMS (ES) [M+1]⁺ m/z 366.2.

Example 1.91 Synthesis of2-{methyl[2-(4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(3-methyloxolan-3-yl)acetamide(Compound 65)

Compound 65 was synthesized similar to compound 62 by replacing2-amino-2-methyl-1-propanol with 3-methyloxolan-3-amine. ¹H NMR (300MHz, DMSO-d₆) δ 8.51 (d, J=4.9 Hz, 1H), 8.20 (s, 1H), 8.16 (d, J=1.8 Hz,1H), 7.27 (dd, J=5.1, 1.4 Hz, 1H), 4.18 (s, 2H), 3.80 (d, J=8.7 Hz, 1H),3.77-3.67 (m, 2H), 3.49 (d, J=8.7 Hz, 1H), 3.29 (s, 3H), 3.16 (t, J=7.4Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.40 (s, 3H), 2.12-2.28 (m, 1H),1.81-2.02 (m, 2H), 1.71-1.79 (m, 1H), 1.31 (s, 3H). LCMS (ES) [M+1]⁺m/z: 382.3.

Example 1.92 Synthesis ofN-(3-fluorophenyl)-2-{methyl[2-(4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 66)

Compound 66 was synthesized similar to compound 62 by replacing2-amino-2-methyl-1-propanol with 3-fluoroaniline. ¹H NMR (300 MHz,DMSO-d₆) δ 10.49 (s, 1H), 8.47 (d, J=4.9 Hz, 1H), 8.03 (s, 1H),7.65-7.55 (m, 1H), 7.39-7.26 (m, 2H), 7.25-7.17 (m, 1H), 6.93-6.80 (m,1H), 4.40 (s, 2H), 3.39 (s, 3H), 3.22 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.8Hz, 2H), 2.18 (s, 3H), 2.11-1.94 (m, 2H). LCMS (ES) [M+1]⁺ m/z 392.1.

Example 1.93 Synthesis ofN-tert-butyl-2-{methyl[2-(pyrimidin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino}acetamide(Compound 67)

Scheme 56 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 40-mL vial purged and maintained in an inert atmosphere ofnitrogen was placed 2,4-dichloro-5H,6H,7H-cyclopenta[b]pyridine (500.00mg, 2.66 mmol, 1.00 equiv), 2-(tributylstannyl)pyrimidine (1275.94 mg,3.46 mmol, 1.30 equiv), CsF (807.78 mg, 5.32 mmol, 2.00 equiv),Pd(PPh₃)₄ (307.25 mg, 0.26 mmol, 0.10 equiv), CuI (50.64 mg, 0.26 mmol,0.10 equiv), and DMF (10.00 mL). The resulting solution was stirred for8 h at 110° C. The reaction mixture was cooled to room temperature. Thecrude product (1 g) was purified by Prep-HPLC with the followingconditions: Column, XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um;mobile phase, Water (0.1% NH₄HCO₃) and CAN (30% Phase B up to 60% in 11min); Detector, 254 nm. This resulted in 200 mg (32.47%) of2-[4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]pyrimidine as a brownsolid. LCMS (ES) [M+H]⁺ m/z: 232.

Step 2

Into a 40-mL vial purged and maintained in an inert atmosphere ofnitrogen, was placed2-[4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]pyrimidine (150.00 mg,0.65 mmol, 1.00 equiv), N-tert-butyl-2-(methylamino)acetamide (121.39mg, 0.84 mmol, 1.30 equiv), Pd(OAc)₂ (14.54 mg, 0.06 mmol, 0.10 equiv),BINAP (80.63 mg, 0.13 mmol, 0.20 equiv), Cs₂CO₃ (421.90 mg, 1.29 mmol,2.00 equiv), and dioxane (8.00 mL). The resulting solution was stirredovernight at 100° C. The reaction mixture was cooled to roomtemperature. The resulting mixture was concentrated. The crude product(500 mg) was purified by Prep-HPLC with the following conditions:Column, XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um; mobile phase,Water (0.1% HCOOH) and CAN (20% Phase B up to 50% in 11 min); Detector,254 nm. This resulted in 82.1 mg (32.90%) ofN-tert-butyl-2-[methyl[2-(pyrimidin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino]acetamideformate as a yellow oil. ¹H-NMR (300 MHz, DMSO-d6) δ 8.91 (d, J=4.8 Hz,2H), 8.17 (s, 1H), 7.61 (s, 1H), 7.57-7.45 (m, 2H), 3.98 (s, 2H), 3.09(s, 3H), 3.04 (t, J=7.2 Hz, 2H), 2.88 (t, J=7.7 Hz, 2H), 2.09-1.93 (m,2H), 1.27 (s, 9H). LCMS (ES, m/z): [M+H]⁺: 340.1.

Example 1.94 Synthesis ofN-tert-butyl-2-{methyl[2-(4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino}acetamide(Compound 68)

Scheme 57 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 40-mL vial purged and maintained in an inert atmosphere ofnitrogen, was placed 2,4-dichloro-5H,6H,7H-cyclopenta[b]pyridine (500.00mg, 2.66 mmol, 1.00 equiv), 4-methyl-2-(tributylstannyl)pyridine(1321.01 mg, 3.46 mmol, 1.30 equiv), Pd(PPh₃)₄ (307.25 mg, 0.26 mmol,0.10 equiv), and dioxane (10.00 mL). The resulting solution was stirredovernight at 110° C. The reaction mixture was cooled to roomtemperature. The resulting mixture was concentrated. The crude product(1 g) was purified by Prep-HPLC with the following conditions: Column,XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um; mobile phase, Water(0.1% NH₄HCO₃) and CAN (40% Phase B up to 70% in 11 min); Detector, 254.This resulted in 300 mg (46.11%) of2-[4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]-4-methylpyridine as awhite solid. LCMS (ES) [M+H]⁺ m/z: 245.

Step 2

Into a 40-mL vial purged and maintained in an inert atmosphere ofnitrogen, was placed2-[4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]-4-methylpyridine (200.00mg, 0.82 mmol, 1.00 equiv), N-tert-butyl-2-(methylamino)acetamide(153.22 mg, 1.06 mmol, 1.30 equiv), Pd(OAc)₂ (18.35 mg, 0.08 mmol, 0.10equiv), Cs₂CO₃ (532.56 mg, 1.64 mmol, 2.00 equiv), BINAP (101.78 mg,0.16 mmol, 0.20 equiv), dioxane (8.00 mL). The resulting solution wasstirred overnight at 100° C. The reaction mixture was cooled to roomtemperature. The resulting mixture was concentrated. The crude product(0.5 g) was purified by Prep-HPLC with the following conditions: Column,XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um; mobile phase, Water(0.1% NH₄HCO₃) and CAN (40% Phase B up to 70% in 11 min); Detector, 254nm. This resulted in 118.1 mg (41.00%) ofN-tert-butyl-2-[methyl[2-(4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino]acetamideas a white solid. ¹H-NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=4.9 Hz, 1H),8.16 (d, J=1.8 Hz, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.19 (dd, J=5.0, 1.8Hz, 1H), 3.93 (s, 2H), 3.06 (s, 3H), 3.02 (t, J=7.1 Hz, 2H), 2.85 (t,J=7.7 Hz, 2H), 2.39 (s, 3H), 2.08-1.95 (m, 2H), 1.27 (s, 9H). LCMS (ES,m/z): [M+H]⁺: 353.2.

Example 1.95 Synthesis ofN-[2-(1-cyclobutyl-5-methyl-1H-imidazol-2-yl)ethyl]-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 69)

Scheme 58 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 250-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed3-((tert-butoxycarbonyl)amino)propanoic acid (7.56 g, 39.955 mmol, 1.00equiv), DCM (100.00 mL), and CDI (6.48 g, 39.955 mmol, 1 equiv). Theresulting solution was stirred for 2 h at room temperature. This wasfollowed by the addition of 2-propynylamine (2.20 g, 39.942 mmol, 1.00equiv) dropwise with stirring at room temperature. The resultingsolution was stirred overnight at room temperature. The resultingmixture was concentrated. The residue was applied onto a silica gelcolumn and eluted with PE/THF (50% THF). This resulted in 3 g (33.18%)of tert-butyl (3-oxo-3-(prop-2-yn-1-ylamino)propyl)carbamate as anoff-white solid. LCMS (ES) [M+1]⁺ m/z 227.

Step 2

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed tert-butyl(3-oxo-3-(prop-2-yn-1-ylamino)propyl)carbamate (500.00 mg, 2.210 mmol,1.00 equiv), cyclobutylamine (188.59 mg, 2.652 mmol, 1.20 equiv), zinctrifluoromethanesulfonate (160.67 mg, 0.442 mmol, 0.20 equiv), andToluene (30.00 mL). The resulting solution was stirred overnight at 100°C. in an oil bath. The reaction mixture was cooled to room temperaturewith a water bath. The pH value of the solution was adjusted to 8 withK₂CO₃ (10%). The resulting solution was extracted with 3×100 mL of ethylacetate, he organic layers were combined, dried over anhydrous sodiumsulfate, and concentrated. This resulted in 600 mg (crude) of tert-butyl(2-(1-cyclobutyl-5-methyl-1H-imidazol-2-yl)ethyl)carbamate as a yellowoil. LCMS (ES) [M+1]⁺ m/z 280.

Step 3

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed tert-butyl(2-(1-cyclobutyl-5-methyl-1H-imidazol-2-yl)ethyl)carbamate (600.00 mg,2.148 mmol, 1.00 equiv), HCl (gas) in EA (10.00 mL). The resultingsolution was stirred overnight at room temperature. The resultingmixture was concentrated. The solids were isolated by filtration anddried over vacuum. This resulted in 300 mg (77.92%) of2-(1-cyclobutyl-5-methyl-1H-imidazol-2-yl)ethan-1-amine as a yellowsolid. LCMS (ES) [M+1]⁺ m/z 180.

Step 4

Into a 100-mL round-bottom flask, was placedN-methyl-N-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycine(200.00 mg, 0.703 mmol, 1.00 equiv),2-(1-cyclobutyl-5-methyl-1H-imidazol-2-yl)ethan-1-amine (151.32 mg,0.844 mmol, 1.20 equiv), HATU (294.21 mg, 0.774 mmol, 1.10 equiv), DIEA(272.74 mg, 2.110 mmol, 3.00 equiv), and DCM (20.00 mL). The resultingsolution was stirred for 4 hr at room temperature. The resulting mixturewas concentrated. The crude product was purified by Flash-Prep-HPLC(Prep-C18, 20-45M, 120 g, Tianjin Bonna-Agela Technologies; gradientelution of 35% MeCN in water to 60% MeCN in water over a 10 min period,where both solvents contain 0.1% NH₃H₂O). This resulted in 100.6 mg(32.10%) ofN-(2-(1-cyclobutyl-5-methyl-1H-imidazol-2-yl)ethyl)-2-(methyl(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 8.66 (d, J=3.6 Hz,1H), 8.22-8.35 (m, 2H), 7.86 (td, J=7.7, 1.9 Hz, 1H), 7.49-7.38 (m, 1H),6.40 (s, 1H), 4.41-4.56 (m, 1H), 4.19 (s, 2H), 3.25-3.39 (m, 2H), 3.28(s, 3H), 3.15 (t, J=7.4 Hz, 2H), 2.82 (t, J=7.9 Hz, 2H), 2.70 (t, J=7.3Hz, 2H), 2.45-2.23 (m, 4H), 2.18 (s, 3H), 1.87-2.05 (m, 2H), 1.55-1.71(m, 2H). LCMS (ES) [M+1]⁺ m/z 446.2.

Example 1.96 Synthesis ofN-[5-(azepan-1-yl)-1,3,4-thiadiazol-2-yl]-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 70)

Scheme 59 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 50-mL round-bottom flask was placed5-bromo-1,3,4-thiadiazol-2-amine (500 mg, 2.78 mmol, 1.0 equiv), DMF(10.0 mL), K₂CO₃ (1.15 g, 8.33 mmol, 3.0 equiv), and hexamethyleneimine(276 mg, 2.78 mmol, 1.0 equiv). The mixture was stirred for 12 h at 80°C. in an oil bath. After being cooled to room temperature, the reactionwas diluted with 20 mL of water and extracted with 3×20 mL of ethylacetate. The combined organic phase was washed with 3×20 ml of brine,dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column with ethyl acetate/petroleum ether (1:1). This resulted in450 mg (82%) of 5-(azepan-1-yl)-1,3,4-thiadiazol-2-amine obtained as apink solid.

Step 2

Into a 20-mL vial, was placed 5-(azepan-1-yl)-1,3,4-thiadiazol-2-amine(230 mg, 1.16 mmol, 1.1 equiv), DMF (3.0 mL),[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]aceticacid (300 mg, 1.06 mmol, 1.0 equiv), and DIEA (682 mg, 5.28 mmol, 5.0equiv). This was followed by the addition of EDC·HCl (243 mg, 1.27 mmol,1.2 equiv) and HOBt (171 mg, 1.27 mmol, 1.2 equiv) at 0° C. The mixturewas stirred for 1 h at room temperature. The reaction solution waspurified by Prep-HPLC with conditions: C18-120 g column, CH₃CN/H₂O (0.5%NH₄OH) from 5% to 80% within 15 min, flow rate: 70 mL/min, detector, 254nm. 106.6 mg (22%) ofN-[5-(azepan-1-yl)-1,3,4-thiadiazol-2-yl]-2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamidewas obtained as off-white solid. ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 12.19(br, 1H), 8.64 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.19 (dt, J=7.9, 1.1 Hz,1H), 7.77 (td, J=7.7, 1.8 Hz, 1H), 7.41 (ddd, J=7.5, 4.7, 1.2 Hz, 1H),4.50 (s, 2H), 3.48 (t, J=5.7 Hz, 4H), 3.36 (s, 3H), 3.20 (t, J=7.2 Hz,2H), 2.84 (t, J=7.8 Hz, 2H), 2.06-1.96 (m, 2H), 1.73-1.67 (m, 4H),1.50-1.46 (m, 4H). LCMS (ES, m/z): [M+H]⁺: 465.3.

Example 1.97 Synthesis of1-[2-(1,3-thiazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane(Compound 94)

Compound 94 was synthesized similar to Compound 92 by replacing2-(tributylstannyl)pyridine with 4-(tributylstannyl)thiazole. ¹H NMR(400 MHz, DMSO-d₆) δ 9.13 (d, J=2.1 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H),3.75 (t, J=6.1 Hz, 4H), 3.05 (t, J=7.3 Hz, 2H), 2.78 (t, J=7.9 Hz, 2H),1.97 (p, J=7.7 Hz, 2H), 1.73 (q, J=5.5 Hz, 4H), 1.47 (p, J=2.8 Hz, 4H).LCMS (ES) [M+1]⁺ m/z: 301.2.

Example 1.98 Synthesis of3-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-1-phenylpyrrolidin-2-one(Compound 95)

Compound 95 was synthesized similar to Compound 73 by replacing2-pyridinylmethanamine with 3-amino-1-phenylpyrrolidin-2-one LCMS (ES+):(M+H)⁺=386.3. ¹H NMR (400 MHz, DMSO-d6) δ 8.65-8.45 (m, 1H), 8.23-8.06(m, 1H), 7.79-7.56 (m, 3H), 7.44-7.08 (m, 4H), 5.48-5.17 (m, 1H),4.01-3.85 (m, 2H), 3.24 (s, 5H), 2.90-2.79 (m, 2H), 2.44-2.27 (m, 2H),2.09-1.95 (m, 2H).

Example 1.99 Synthesis of1-[2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane(Compound 96)

Compound 96 was synthesized similar to Compound 92 by replacing2-(tributylstannyl)pyridine with 4-chloro-2-(tributylstannyl)pyridine.¹H NMR (400 MHz, Methanol-d₄) δ 8.59 (d, J=5.3 Hz, 1H), 8.30 (d, J=2.0Hz, 1H), 7.50 (dd, J=5.3, 2.1 Hz, 1H), 3.81 (t, J=6.1 Hz, 4H), 3.11 (t,J=7.3 Hz, 2H), 2.89 (t, J=7.9 Hz, 2H), 2.07 (p, J=7.7 Hz, 2H), 1.81 (dq,J=9.2, 4.0 Hz, 4H), 1.51 (m, 4H). LCMS (ES) [M+1]⁺ m/z: 329.3, 331.4.

Example 1.100 Synthesis of1-[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane(Compound 97)

Compound 97 was synthesized similar to Compound 92 by replacing2-(tributylstannyl)pyridine with1-methyl-4-(tributylstannyl)-1H-imidazole. ¹H NMR (400 MHz, Methanol-d4)δ 7.86 (d, J=1.3 Hz, 1H), 7.73 (d, J=1.3 Hz, 1H), 3.88 (t, J=6.1 Hz,4H), 3.80 (s, 3H), 3.12 (t, J=7.4 Hz, 2H), 2.91 (t, J=7.9 Hz, 2H), 2.09(h, J=8.1 Hz, 2H), 1.82 (q, J=5.7 Hz, 4H), 1.58 (p, J=2.7 Hz, 4H). LCMS(ES) [M+1]⁺ m/z: 298.2.

Example 1.101 Synthesis of2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-[1-(trifluoromethyl)cyclopropyl]acetamide(Compound 98)

Scheme 60 depicts a synthetic route for preparing an exemplary compound.

Step 1

To a solution of [(tert-butoxycarbonyl)(methyl)amino]acetic acid (302.51mg; 1.60 mmol; 1.00 eq.) in DMF (2.5 mL) was added1-(trifluoromethyl)cyclopropan-1-amine (200.00 mg; 1.60 mmol; 1.00 eq.),followed by DIPEA (0.42 mL; 2.40 mmol; 1.50 eq.) and HATU (607.92 mg;1.60 mmol; 1.00 eq.). After being stirred for 15 h at room temperature,it was diluted with water, and extracted with EtOAc. The organic layerswere combined, dried, and concentrated to give tert-butylN-methyl-N-({[1-(trifluoromethyl)cyclopropyl]carbamoyl}methyl)carbamate,which was used for the next step without purification. LCMS (ES) [M+1]⁺m/z: 297.5.

Step 2

To a solution of tert-butylN-methyl-N-({[1-(trifluoromethyl)cyclopropyl]carbamoyl}methyl)carbamate(0.47 g; 1.60 mmol; 1.00 eq.) in DCM (4 mL) was added 4N HCl in dioxane(4 mL). The mixture was stirred further, concentrated, and lyophilizedto give2-[chloro(methyl)amino]-N-[1-(trifluoromethyl)cyclopropyl]acetamide,which was used directly for the next step without purification. LCMS(ES) [M+1]⁺ m/z: 197.3.

Step 3

To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.13 g; 0.70 mmol; 1.00 eq.) in AcCN (2 mL) was added2-[chloro(methyl)amino]-N-[1-(trifluoromethyl)cyclopropyl]acetamide(0.19 g; 0.80 mmol; 1.15 eq.), and triethylamine (0.29 mL; 2.10 mmol;3.00 eq.). After being heated at 75° C. for 4 h, the mixture was cooledand concentrated, diluted with water, and the resulting precipitateswere collected by filtration and dried to give2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-[1-(trifluoromethyl)cyclopropyl]acetamide(200 mg). LCMS (ES) [M+1]⁺ m/z: 349.0, 351.1.

Step 4

To a solution of2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-[1-(trifluoromethyl)cyclopropyl]acetamide(50.00 mg; 0.20 mmol; 1.00 eq.) and 2-(tributylstannyl)pyridine (190.01mg; 0.52 mmol; 2.00 eq.) in toluene (1 mL) was addedtetrakis(triphenylphosphane) palladium (29.82 mg; 0.03 mmol; 0.10 eq.).The mixture was heated at 115° C. for 15 h. The mixture was cooled andconcentrated, and the crude residue was purified by preparative HPLC togive2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-[1-(trifluoromethyl)cyclopropyl]acetamide(49.8 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (s, 1H), 8.80 (d, J=4.7 Hz,1H), 8.35 (d, J=8.2 Hz, 1H), 8.07 (s, 1H), 7.70 (s, 1H), 4.37 (s, 2H),3.44 (s, 3H), 3.20 (m, 2H), 3.00 (t, J=7.9 Hz, 2H), 2.11-2.03 (m, 2H),1.25-1.17 (m, 2H), 0.96 (s, 2H). LCMS (ES) [M+1]⁺ m/z: 392.0.

Example 1.102 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-[1-(trifluoromethyl)cyclopropyl]acetamide(Compound 99)

Compound 99 was synthesized similar to Compound 98 by replacing2-(tributylstannyl)pyridine with 4-methoxy-2-(tributylstannyl)pyridine.¹H NMR (400 MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.65 (d, J=6.1 Hz, 1H), 7.91(d, J=2.6 Hz, 1H), 7.41 (dd, J=6.2, 2.6 Hz, 1H), 4.35 (s, 2H), 4.02 (s,3H), 3.40 (s, 3H), 3.22 (m, 2H), 2.96 (t, J=7.9 Hz, 2H), 2.11-1.99 (m,2H), 1.23-1.09 (m, 2H), 0.96 (s, 2H). LCMS (ES) [M+1]⁺ m/z: 421.7.

Example 1.103 Synthesis ofN-tert-butyl-2-{[2-(4-ethylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 100)

Scheme 61 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed 2-bromo-4-ethylpyridine (500 mg, 2.68mmol, 1.00 equiv), dioxane (5.0 mL), hexamethyldistannane (1.06 g, 3.22mmol, 1.20 equiv), and Pd(dppf)Cl₂ (196 mg, 0.26 mmol, 0.10 equiv). Themixture was stirred for 2 h at 100° C. The reaction mixture was cooledand diluted with 20 mL of H₂O and extracted with 3×10 mL of ethylacetate. The combined organic phase was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. This resulted in 600 mg crude product of4-ethyl-2-(trimethylstannyl)pyridine as a brown oil, which was used inthe next step directly without further purification. LCMS (ES): [M+1]⁺m/z: 272.

Step 2

Into a 50-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placedN-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(300 mg, 1.01 mmol, 1.00 equiv), dioxane (5.0 mL),4-ethyl-2-(trimethylstannyl)pyridine (409 mg, 1.51 mmol, 1.50 equiv),and Pd(dppf)Cl₂ (73 mg, 0.10 mmol, 0.10 equiv). The mixture was stirredfor 16 hat 100° C. The reaction mixture was cooled and diluted with 20mL of H₂O and extracted with 3×10 mL of ethyl acetate. The combinedorganic phase was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated. The crude residue was purified by Prep-HPLCwith the following conditions: Column, Kinetex EVO C18 Column, 21.2*150,5 um, mobile phase, Water (0.1% FA) and CH₃CN (10% Phase B up to 50% in15 min); Detector, UV 254 nm. 29.6 mg (7.9%) ofN-tert-butyl-2-[[2-(4-ethylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamidewas obtained as a pink solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (d, J=4.8Hz, 1H), 8.16 (s, 1H), 7.69 (s, 1H), 7.30 (dd, J=5.1, 1.7 Hz, 1H), 4.16(s, 2H), 3.27 (s, 3H), 3.15 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H),2.72 (q, J=7.5 Hz, 2H), 2.08-1.91 (m, 2H), 1.30-1.19 (m, 12H). LCMS (ES)[M+1]⁺ m/z: 368.2.

Example 1.104 Synthesis of(2R)—N-tert-butyl-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}propanamide(Compound 101)

Scheme 62 depicts a synthetic route for preparing an exemplary compound.

Step 1

(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]propanoic acid (0.5 g; 2.46mmol; 1 eq.) was dissolved in dichloromethane (20 ml) and cooled in anice bath. Tert-butylamine (0.28 mL; 2.71 mmol; 1.1 eq.),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 1.03 g; 2.71 mmol; 1.1 eq.) andN,N-diisopropylethylamine (0.90 mL; 5.17 mmol; 2.1 eq.) were then added.The reaction was stirred to 25° C. over 20 h and then taken up in ethylacetate (100 ml), water (10 ml), and sodium bicarbonate solution (50ml). The phases were separated, and the aqueous phase was extracted withmore ethyl acetate (100 ml). The combined organics were washed withsodium chloride solution (30 ml), dried over sodium sulfate, andevaporated. The residue was purified by silica gel chromatography (ethylacetate/hexanes gradient) to give tert-butylN-[(1R)-1-(tert-butylcarbamoyl)ethyl]-N-methylcarbamate (0.61 g, 96%) asa white solid. LCMS (ES+): (M+Na)⁺=281.0.

Step 2

Tert-butylN-{1-[(1-hydroxy-3-phenylpropan-2-yl)carbamoyl]ethyl}-N-methylcarbamate(0.56 g; 1.66 mmol; 1 eq.) was dissolved in dichloromethane (8 ml) andcooled in an ice bath. Trifluoroacetic acid (4 ml) was added slowly andthe reaction was stirred to 25° C. over 3 h. The reaction wasevaporated, and the residue was co-evaporated with toluene and driedunder high vacuum to give (2R)—N-tert-butyl-2-(methylamino)propanamide;trifluoroacetic acid, which was used directly in the next step. LCMS(ES+): (M+Na)⁺=159.0.

Step 3

2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (400.00 mg; 2.12mmol; 1.00 eq.) (Combi-Blocks) was dissolved in acetonitrile (7 ml), andto this was added (2R)—N-tert-butyl-2-(methylamino)propanamide;trifluoroacetic acid (633.70 mg; 2.33 mmol; 1.10 eq.), and Hunig's base(1.84 mL; 10.58 mmol; 5.00 eq.). The mixture was stirred at 70° C. for15 h, the solvent was then evaporated under reduced pressure, and theresidue was purified by column chromatography (50% EtOAc in Hexanes) togive(2R)—N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)propenamide(480 mg, 73%). LCMS (ES+): (M+H)⁺=310.9.

Step 4

(2R)—N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)propanamide(140.00 mg; 0.45 mmol; 1.00 eq.) was dissolved in 1,4-dioxane (3.5 ml)and the solution was purged with Ar gas.4-methoxy-2-(tributylstannyl)pyridine (0.36 g; 0.90 mmol; 2.00 eq.) andtetrakis(triphenylphosphane) palladium (52.05 mg; 0.05 mmol; 0.10 eq.)were added. The reaction vessel was sealed and stirred in a heat bath at110° C. for 15 h. After evaporation, the residue was purified by reversephase chromatography (Waters XSelect CSH C18 column, 0-70%acetonitrile/0.1% aqueous formic acid gradient) to give(2R)—N-tert-butyl-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}propanamide(67 mg, 39%) as a white solid. LCMS (ES+): (M+H)⁺=384.4. ¹H NMR (400MHz, Methanol-d4) δ 8.51 (d, J=5.8 Hz, 1H), 7.95 (d, J=2.6 Hz, 1H), 7.63(s, 1H), 7.09 (dd, J=5.8, 2.6 Hz, 1H), 5.24 (q, J=7.1 Hz, 1H), 3.98 (s,3H), 3.30-3.15 (m, 5H), 3.04-2.86 (m, 2H), 2.21-2.01 (m, 2H), 1.45 (d,J=7.1 Hz, 3H), 1.23 (s, 9H).

Example 1.105 Synthesis ofN-tert-butyl-2-({2-[4-(dimethylamino)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 102)

Scheme 63 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 100-mL 3-necked round-bottom flask purged and maintained in aninert atmosphere of nitrogen was placed ethanolamine (1.00 g, 16.371mmol, 2.00 equiv) and THE (40.00 mL). This was followed by the additionof n-BuLi (13.00 mL, 138.006 mmol, 16.86 equiv) dropwise with stirringat 0° C. in 10 min. The resulting solution was stirred for 0.5 h at 0°C. To this was added a solution of 4-dimethylaminopyridine (1.00 g,8.185 mmol, 1.00 equiv) in THE (5 mL) dropwise with stirring at 0° C. in5 min. The resulting solution was stirred for 1 h at 0° C. The resultingsolution was stirred for 0.5 h at room temperature. To the mixture wasadded tributyltin chloride (6.66 g, 20.460 mmol, 2.50 equiv) dropwisewith stirring at −78° C. in 10 min. The resulting solution was thenstirred overnight at room temperature. The resulting solution wasdiluted with 50 mL of H₂O and extracted with 3×50 mL of dichloromethane.The organic layers were combined, dried over anhydrous sodium sulfate,and concentrated. The residue was applied onto a silica gel column andeluted with ethyl acetate/petroleum ether (20%-50% EA). This resulted in0.8 g (23.77%) of N,N-dimethyl-2-(tributylstannyl)pyridin-4-amine as ayellow oil. LCMS (ES) [M+1]⁺ m/z 413.2.

Step 2

Into a 40-mL round-bottom flask purged and maintained in an inertatmosphere of argon, was placedN,N-dimethyl-2-(tributylstannyl)pyridin-4-amine (418.00 mg, 1.016 mmol,1.00 equiv),N-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(301.69 mg, 1.016 mmol, 1.00 equiv), Pd(PPh₃)₄ (117.46 mg, 0.102 mmol,0.10 equiv), and dioxane (10.00 mL). The resulting solution was stirredfor 24 hr at 100° C. in an oil bath. The resulting mixture wasconcentrated. The residue was applied onto a silica gel column andeluted with dichloromethane/methanol (10%-30% MeOH). The collected crudeproduct was purified by Flash-Prep-HPLC (Prep-C18, 20-45M, 120 g,Tianjin Bonna-AgelaTechnologies; gradient elution of 20% MeCN in waterto 45% MeCN in water over a 10 min period, where both solvents contain0.1% FA). This resulted in 44.9 mg (11.55%) ofN-(tert-butyl)-2-((2-(4-(dimethylamino)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideformate as a light yellow solid. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 8.23(s, 1H), 8.21 (d, J=6.0 Hz, 1H), 7.68 (s, 1H), 7.59 (d, J=2.7 Hz, 1H),6.72 (dd, J=6.2, 2.8 Hz, 1H), 4.17 (s, 2H), 3.13 (t, J=7.3 Hz, 2H), 3.07(s, 6H), 2.82 (t, J=7.7 Hz, 2H), 1.89-2.08 (m, 2H), 1.22 (s, 9H). LCMS(ES) [M+1]⁺ m/z 383.2.

Example 1.106 Synthesis ofN-tert-butyl-2-{methyl[2-(3-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 103)

Scheme 64 depicts a synthetic route for preparing an exemplary compound.

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placedN-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(800.00 mg, 2.695 mmol, 1.00 equiv),3-methyl-2-(tributylstannyl)pyridine (1.23 g, 3.235 mmol, 1.20 equiv),Pd(dppf)Cl₂ (197.22 mg, 0.270 mmol, 0.10 equiv), CsF (409.44 mg, 2.695mmol, 1.00 equiv), and dioxane (20.00 mL). The resulting solution wasstirred for 16 hr at 120° C. The reaction mixture was cooled. Theresulting solution was extracted with 3×50 mL of dichloromethane. Theorganic layers were combined, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The crude product was purified by Prep-HPLCwith the following conditions (Prep-HPLC-002): Column, XBridge BEH130Prep C18 OBD Column, 19*150 mm 5 um 13 nm; mobile phase, Water (0.05%FA) and ACN (10% PhaseB up to 50% in 8 min). This resulted in 41.3 mg(4.3%) ofN-tert-butyl-2-[methyl[2-(3-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamideformate as a pink solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.41 (d, J=4.7 Hz,1H), 8.19 (s, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.49 (s, 1H), 7.31 (dd,J=7.7, 4.7 Hz, 1H), 4.11 (s, 2H), 3.18 (s, 3H), 3.14 (d, J=7.4 Hz, 2H),2.78 (t, J=7.8 Hz, 2H), 2.28 (s, 3H), 2.05-1.95 (m, 2H), 1.22 (s, 9H).LCMS (ES) [M+1]⁺ m/z: 354.2.

Example 1.107 Synthesis ofN-tert-butyl-2-{methyl[2-(5-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 104)

Scheme 65 depicts a synthetic route for preparing an exemplary compound.

Into a 40-mL vial purged and maintained in an inert atmosphere ofnitrogen, was placedN-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(500 mg, 1.69 mmol, 1.0 equiv), 5-methyl-2-(tributylstannyl)pyridine(712 mg, 1.86 mmol, 1.1 equiv), dioxane (5.0 mL), and Pd(PPh₃)₄ (391 mg,0.34 mmol, 0.2 equiv). The mixture was stirred for 12 h at 100° C. Itwas then concentrated to remove the solvent, and the crude product waspurified by Prep-HPLC with the following conditions: Column, AtlantisHILIC OBD Column, 19*150 mm*5 um, Mobile phase, Water (0.1% FA) andCH₃CN (5% Phase B up to 35% in 8 min), Detector, UV 254 nm. Thisresulted 48.3 mg (7%) ofN-(tert-butyl)-2-(methyl(2-(5-methylpyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamideformate as a light brown solid. ¹HNMR (300 MHz, DMSO-d₆, ppm): δ 8.50(d, J=2.1 Hz, 1H), 8.26 (d, J=8.1 Hz, 1H), 8.18 (s, 1H), 7.70-7.68 (m,2H), 4.13 (s, 2H), 3.26 (s, 3H), 3.14 (t, J=7.2 Hz, 2H), 2.81 (t, J=7.8Hz, 2H), 2.36 (s, 3H), 2.01-1.96 (m, 2H), 1.24 (s, 9H). LCMS (ES, m/z):[M+H]⁺: 354.1.

Example 1.108 Synthesis of2-{methyl[2-(4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(1-methylcyclopentyl)acetamide(Compound 105)

Compound 105 was synthesized similar to compound 62 by replacing2-amino-2-methyl-1-propanol with 1-methylcyclopentanamine. ¹H NMR (300MHz, DMSO-d₆, ppm) δ 8.51 (d, J=4.9 Hz, 1H), 8.16 (s, 1H), 7.76 (s, 1H),7.27 (dd, J=5.2, 1.7 Hz, 1H), 4.16 (s, 2H), 3.28 (s, 3H), 3.15 (t, J=7.3Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.41 (s, 3H), 2.07-1.89 (m, 4H),1.60-1.40 (m, 6H), 1.28 (s, 3H). LCMS (ES) [M+1]⁺ m/z 380.2.

Example 1.109 Synthesis ofN-tert-butyl-2-{methyl[2-(pyrimidin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 106)

Scheme 66 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 40-mL vial purged and maintained in an inert atmosphere ofnitrogen, was placed 2,4-dichloro-5H,6H,7H-cyclopenta[b]pyridine (500.00mg, 2.66 mmol, 1.00 equiv), 2-(tributylstannyl)pyrimidine (1275.94 mg,3.46 mmol, 1.30 equiv), CsF (807.78 mg, 5.32 mmol, 2.00 equiv),Pd(PPh₃)₄ (307.25 mg, 0.26 mmol, 0.10 equiv), CuI (50.64 mg, 0.26 mmol,0.10 equiv), and DMF (10.00 mL). The resulting solution was stirred for8 h at 110° C. The reaction mixture was cooled to room temperature. Thecrude product (1 g) was purified by Prep-HPLC with the followingconditions: Column, XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um;mobile phase, Water (0.1% NH₄HCO₃) and CAN (30% Phase B up to 60% in 11min); Detector, 254. This resulted in 200 mg (32.47%) of2-[4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]pyrimidine as a brownsolid. LCMS (ES) [M+H]⁺ m/z: 232.

Step 2

Into a 40-mL vial purged and maintained in an inert atmosphere ofnitrogen was placed2-[4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]pyrimidine (150.00 mg,0.65 mmol, 1.00 equiv), N-tert-butyl-2-(methylamino)acetamide (121.39mg, 0.84 mmol, 1.30 equiv), Pd(OAc)₂ (14.54 mg, 0.06 mmol, 0.10 equiv),BINAP (80.63 mg, 0.13 mmol, 0.20 equiv), Cs₂CO₃ (421.90 mg, 1.29 mmol,2.00 equiv), and dioxane (8.00 mL). The resulting solution was stirredovernight at 100° C. The reaction mixture was cooled to room temperatureand concentrated. The crude product (500 mg) was purified by Prep-HPLCwith the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150 mm, 5 um; mobile phase, Water (0.1% HCOOH) and CAN (20% Phase Bup to 50% in 11 min); Detector, 254. This resulted in 82.1 mg (32.90%)ofN-tert-butyl-2-[methyl[2-(pyrimidin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino]acetamideformate as a yellow oil. ¹HNMR (300 MHz, DMSO-d6) δ 8.91 (d, J=4.8 Hz,2H), 8.17 (s, 1H), 7.61 (s, 1H), 7.57-7.45 (m, 2H), 3.98 (s, 2H), 3.09(s, 3H), 3.04 (t, J=7.2 Hz, 2H), 2.88 (t, J=7.7 Hz, 2H), 2.09-1.93 (m,2H), 1.27 (s, 9H). LCMS (ES, m/z): [M+H]⁺: 341.2.

Example 1.110 Synthesis ofN-tert-butyl-2-({2-[5-(2-hydroxyethyl)-1,3-thiazol-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 107)

Scheme 67 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 250-mL round-bottom flask, was placed 4-(benzyloxy)butan-1-ol(5.00 g, 27.74 mmol, 1.00 equiv), DCM (100 mL), and PCC (11.96 g, 55.47mmol, 2.00 equiv). The mixture was stirred for 16 h at room temperature,filtered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column and eluted with ethylacetate/petroleum ether (1/10). This resulted in 2.5 g (50%) of4-(benzyloxy)butanal was obtained as a colorless solid. LCMS (ES)[M+1]⁺m/z: 179.

Step 2

Into a 100-mL 3-necked round-bottom flask, was placed4-(cyclohexylmethoxy)butan-1-ol (2.50 g, 13.42 mmol, 1.00 equiv), DMSO(30 mL). This was followed by the addition of bromotrimethylsilane (2.05g, 13.42 mmol, 1.00 equiv) dropwise with stirring at 0° C. The resultingsolution was stirred for 6 h at room temperature. The reaction wasquenched with 100 mL of H₂O, extracted with 3×30 mL of ethyl acetate,the organic layers were combined and dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated. The residue waspurified by silica gel column with ethyl acetate/petroleum ether (1/10).This resulted in 1.5 g (43.4%) of 4-(benzyloxy)-2-bromobutanal as lightbrown oil. LCMS (ES) [M+1]⁺ m/z: 257.

Step 3

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen was placedN-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(600 mg, 2.02 mmol, 1.00 equiv), DMA (6.0 mL), Zn(CN)₂ (474 mg, 4.04mmol, 2.00 equiv), Zn (264 mg, 4.04 mmol, 2.00 equiv), and Pd(dppf)Cl₂(147 mg, 0.20 mmol, 0.10 equiv). The mixture was stirred for 2 h at 100°C. The reaction mixture was cooled and filtered. The filtrate wasdiluted with 20 mL of H₂O, extracted with 3×20 mL of ethyl acetate, theorganic layers were combined and dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated. The residue was purified bysilica gel column with ethyl acetate/petroleum ether (1/1). Thisresulted in 550 mg (95%) ofN-tert-butyl-2-([2-cyano-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamideas a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.64 (s, 1H), 4.10 (s,2H), 3.18 (s, 3H), 3.13 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.8 Hz, 2H),2.04-1.88 (m, 2H), 1.27 (s, 9H). LCMS (ES) [M+1]⁺ m/z: 288.

Step 4

Into a 100-mL round-bottom flask was placedN-tert-butyl-2-([2-cyano-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(530 mg, 1.84 mmol, 1.00 equiv), DMF (6.0 mL), (NH₄)₂S (251 mg, 3.68mmol, 2.00 equiv), and TEA (373 mg, 3.68 mmol, 2.00 equiv). Theresulting solution was stirred for 0.5 h at room temperature. Thereaction solution was diluted with 20 mL of H₂O, extracted with 3×20 mLof ethyl acetate, the organic layers were combined and dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated.The crude product was washed with 30 ml of hexane. This resulted in 500mg (84.3%) ofN-tert-butyl-2-([2-carbamothioyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamideas a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.10 (br, 1H), 9.45 (br,1H), 7.60 (s, 1H), 4.01 (s, 2H), 3.25 (s, 3H), 3.12 (t, J=7.5 Hz, 2H),2.79 (t, J=7.8 Hz, 2H), 2.04-1.88 (m, 2H), 1.25 (s, 9H). LCMS (ES)[M+1]⁺ m/z: 322.

Step 5

Into a 100-mL round-bottom flask, was placedN-tert-butyl-2-([2-carbamothioyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(400 mg, 1.24 mmol, 1.00 equiv), DMF (5.0 mL), DIEA (321 mg, 2.48 mmol,2.00 equiv), and 4-(benzyloxy)-2-bromobutanal (383 mg, 1.49 mmol, 1.20equiv). The resulting solution was stirred for 16 h at room temperature.The reaction was diluted with 20 mL of H₂O, extracted with 3×20 mL ofethyl acetate, the organic layers were combined and dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated. The residuewas purified by silica gel column with ethyl acetate/petroleum ether(1/10). This resulted in 380 mg (61%) of2-[[2-([[4-(benzyloxy)-1-oxobutan-2-yl]sulfanyl]methanimidoyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-N-tert-butylacetamideas a brown solid. LCMS (ES) [M+1]⁺ m/z: 498.

Step 5

Into a 100-mL round-bottom flask, was placed2-[[2-([[4-(benzyloxy)-1-oxobutan-2-yl]sulfanyl]methanimidoyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-N-tert-butylacetamide(380 mg, 0.76 mmol, 1.00 equiv), and AcOH (4.0 mL). The mixture wasstirred for 1 h at 100° C. The reaction mixture was cooled to roomtemperature, and diluted with 10 mL of H₂O. The pH value of the solutionwas adjusted to 8 with NaHCO₃ (10%), extracted with 3×10 mL of ethylacetate, the organic layers were combined and dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated. The residuewas purified by silica gel column with ethyl acetate/petroleum ether(1/1). 180 mg (49%) of2-[(2-[5-[2-(benzyloxy)ethyl]-1,3-thiazol-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-tert-butylacetamidewas obtained as a brown solid. LCMS (ES) [M+1]⁺ m/z: 480.

Step 6

Into a 50-mL 3-necked round-bottom flask purged and maintained in aninert atmosphere of nitrogen was placed2-[(2-[5-[2-(benzyloxy)ethyl]-1,3-thiazol-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-tert-butylacetamide(180 mg, 0.37 mmol, 1.00 equiv), and DCM (3.0 mL). This was followed bythe addition of BBr₃ (1.8 mL, 1.80 mmol, 4.80 equiv) dropwise withstirring at −78° C. The resulting solution was stirred for 2 h at 0° C.The reaction was then quenched by the addition of 10 mL of water, andextracted with 3×5 mL of dichloromethane. The organic layers werecombined, dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated. The crude product was purified by Prep-HPLCwith the following conditions: Column, Welch XB-C18, 21.2*250 mm, 5 um,Mobile phase, Water (0.05% NH₄OH) and CH₃CN (10% Phase B up to 65% in 15min), Detector, UV 254 nm. This resulted in 53.0 mg (36.2%) ofN-tert-butyl-2-([2-[5-(2-hydroxyethyl)-1,3-thiazol-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.68 (s, 1H), 7.62 (s,1H), 4.91 (t, J=5.1 Hz, 1H), 4.14 (s, 2H), 3.65 (q, J=6.3 Hz, 2H), 3.22(s, 3H), 3.10 (t, J=7.5 Hz, 2H), 2.98 (t, J=6.3 Hz, 2H), 2.79 (t, J=7.8Hz, 2H), 2.06-1.90 (m, 2H), 1.26 (s, 9H). LCMS (ES) [M+1]⁺ m/z: 390.2.

Example 1.111 Synthesis of(2R)—N-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 108)

Step 1

(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]propanoic acid (0.50 g; 2.46mmol; 1.00 eq.) was dissolved in dichloromethane (20 ml) and cooled inan ice bath. Cyclohexanamine (0.31 mL; 2.71 mmol; 1.10 eq.),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 1.03 g; 2.71 mmol; 1.10 eq.)), andHunig's base (0.90 mL; 5.17 mmol; 2.10 eq.) were then added. Thereaction was stirred to 25° C. over 20 h and then taken up in ethylacetate (100 ml), water (10 ml), and sodium bicarbonate solution (50ml). The phases were separated, and the aqueous phase was extracted withmore ethyl acetate (100 ml). The combined organics were washed withsodium chloride solution (30 ml), dried over sodium sulfate, andevaporated. The residue was purified by silica gel chromatography (ethylacetate/hexanes gradient) to give tert-butylN-{1-[(1-hydroxy-3-phenylpropan-2-yl)carbamoyl]ethyl}-N-methylcarbamate(0.7 g, 99%) as a white solid. LCMS (ES+): (M+Na)⁺=307.0.

Step 2

Tert-butylN-{1-[(1-hydroxy-3-phenylpropan-2-yl)carbamoyl]ethyl}-N-methylcarbamate(0.56 g; 1.66 mmol; 1.00 eq.) was dissolved in dichloromethane (8 ml)and cooled in an ice bath. Trifluoroacetic acid (4 ml) was added slowlyand the reaction was stirred to 25° C. over 3 h. The reaction wasevaporated, and the residue was co-evaporated with toluene and driedunder high vacuum to give (2R)—N-cyclohexyl-2-(methylamino)propanamide;trifluoroacetic acid which was used directly in the next step.

Step 3

2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (420.00 mg; 2.22mmol; 1.00 eq.) was dissolved in acetonitrile (7 ml), and to this wasadded (2R)—N-cyclohexyl-2-(methylamino)propanamide; trifluoroacetic acid(729.02 mg; 2.44 mmol; 1.10 eq.), and Hunig's base (1.93 mL; 11.11 mmol;5.00 eq.). The mixture was stirred at 70° C. for 15 h, the solvent wasthen evaporated under reduced pressure, and the residue was purified bycolumn chromatography (50% EtOAc in Hexanes) to give(2R)—N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)propenamide(480 mg, 73%). LCMS (ES+): (M+H)⁺=336.9.

Step 4

(2R)-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-cyclohexylpropanamide(150.00 mg; 0.45 mmol; 1.00 eq.) was dissolved in 1,4-dioxane (3.5 ml),and the solution was purged with Ar gas. 2-(tributylstannyl)pyridine(0.29 mL; 0.89 mmol; 2.00 eq.) and tetrakis(triphenylphosphane)palladium (51.46 mg; 0.04 mmol; 0.10 eq.) were added. The reactionvessel was sealed and stirred in a heat bath at 110° C. for 15 h. Afterevaporation, the residue was purified by reverse phase chromatography(Waters XSelect CSH C18 column, 0-70% acetonitrile/0.1% aqueous formicacid gradient) to give(2R)—N-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(132 mg) as a white solid. LCMS (ES+): (M+H)⁺=380.4. ¹H NMR (400 MHz,DMSO-d6) δ 8.82-8.56 (m, 1H), 8.44-8.27 (m, 1H), 8.27-8.07 (m, 1H),7.99-7.77 (m, 1H), 7.57-7.36 (m, 1H), 5.26-5.04 (m, 1H), 3.65-3.50 (m,1H), 3.23-3.15 (m, 2H), 3.09 (s, 3H), 2.93-2.72 (m, 2H), 2.11-1.89 (m,2H), 1.78-1.61 (m, 2H), 1.61-1.47 (m, 3H), 1.35-1.12 (m, 6H), 1.06-0.89(m, 2H).

Example 1.112 Synthesis of(2R)—N-(3,3-difluorocyclobutyl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 109)

Compound 109 was synthesized similar to Compound 108 by replacingcyclohexylamine with 3,3-difluorocyclobutanamine. LCMS (ES+):(M+H)⁺=388.3. ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=7.1 Hz, 1H),8.72-8.66 (m, 1H), 8.31 (d, J=7.9 Hz, 1H), 7.95-7.88 (m, 1H), 7.51-7.43(m, 1H), 5.15 (q, J=7.0 Hz, 1H), 4.17-4.04 (m, 1H), 3.24-3.14 (m, 2H),3.10 (s, 3H), 2.95-2.58 (m, 5H), 2.49-2.41 (m, 1H), 2.09-1.90 (m, 2H),1.34 (d, J=7.0 Hz, 3H).

Example 1.113 Synthesis ofN-tert-butyl-2-[methyl(2-{1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 110)

Scheme 68 depicts a synthetic route for preparing an exemplary compound.

Step 2

To a stirred solution of 5-bromo-1H-pyrazolo[3,4-c]pyridine (4.00 g,20.200 mmol, 1.00 equiv) in DCM (32.00 mL), THE (32.00 mL), and DMF(2.00 mL) were added DHP (3.80 g, 45.175 mmol, 2.24 equiv) andp-Toluenesulfonic acid (0.35 g, 0.002 mmol, 0.10 equiv) at roomtemperature under an air atmosphere. The resulting mixture was stirredfor 12 h at 50° C. under an air atmosphere. The mixture was allowed tocool down to room temperature. The resulting mixture was concentratedunder reduced pressure. The residue was dissolved in 10% NaHCO₃ (100mL). The resulting mixture was extracted with EtOAc (3×100 mL). Thecombined organic layers were washed with brine (1×100 mL) and dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. This resulted in5-bromo-1-(oxan-2-yl)pyrazolo[3,4-c]pyridine (3 g, 52.64%) as a yellowsolid. LCMS (ES) [M+1]⁺ m/z: 282.

Step 3

To a solution of 5-bromo-1-(oxan-2-yl)pyrazolo[3,4-c]pyridine (71.30 mg,0.253 mmol, 1.5 equiv) and Sn₂Me₆ (91.07 mg, 0.278 mmol, 1.65 equiv) indioxane (2.00 mL) was added Pd(PPh₃)₄ (19.5 mg, 0.017 mmol, 0.1 equiv)after stirring for 2 h at 100° C. under a nitrogen atmosphere. Themixture was cooled to room temperature. To the above mixture was addedN-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(Intermediate II, 50.00 mg, 0.168 mmol, 1.00 equiv), CsF (51.18 mg,0.337 mmol, 2 equiv), and Pd(PPh₃)₄ (19.5 mg, 0.017 mmol, 0.1 equiv) atroom temperature. The resulting mixture was stirred for an additional 16h at 100° C. under a nitrogen atmosphere. The resulting mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography and eluted with PE/THF (1:1) to affordN-tert-butyl-2-[methyl([2-[1-(oxan-2-yl)pyrazolo[3,4-c]pyridin-5-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl])amino]acetamide(50 mg, 64.02%) as a yellow solid. LCMS (ES) [M+1]⁺ m/z: 464.

Step 4

A solution ofN-tert-butyl-2-[methyl([2-[1-(oxan-2-yl)pyrazolo[3,4-c]pyridin-5-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl])amino]acetamide(400.00 mg, 0.863 mmol, 1.00 equiv) in 4NHCl (g) in MeOH (4.00 mL,131.648 mmol, 152.57 equiv) was stirred for 2 h at 60° C. under an airatmosphere. The mixture was cooled to room temperature. The resultingmixture was concentrated under reduced pressure. The crude product (500mg) was purified by Prep-HPLC to affordN-tert-butyl-2-[methyl(2-[1H-pyrazolo[3,4-c]pyridin-5-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamideformate (76 mg, 23.21%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) ¹HNMR (300 MHz, DMSO-d₆) δ 13.71 (br, 3H), 9.09 (s, 1H), 8.81 (d, J=1.2Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.77 (s, 1H), 4.15 (s, 2H), 3.30(s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.06-1.92 (m,2H), 1.22 (s, 9H). LCMS (ES) [M+1]⁺ m/z: 380.2.

Example 1.114 Synthesis of2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-[1-(trifluoromethyl)cyclopropyl]acetamide(Compound 111)

Compound 111 was synthesized similar to Compound 98 by replacing2-(tributylstannyl)pyridine with1-methyl-4-(tributylstannyl)-1H-imidazole. ¹H NMR (400 MHz, DMSO-d₆) δ9.15 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 4.35 (s, 2H), 3.80 (s, 3H),3.36 (s, 3H), 3.14 (s, 2H), 2.92 (t, J=7.9 Hz, 2H), 2.02 (p, J=7.9 Hz,2H), 1.24-1.16 (m, 2H), 0.98 (s, 2H). LCMS (ES) [M+1]⁺ m/z: 395.2.

Example 1.115 Synthesis of(2R)—N-tert-butyl-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 112)

Compound 112 was synthesized similar to Compound 101 replacing with1-methyl-4-(tributylstannyl)-1H-imidazole. ¹H NMR (400 MHz, DMSO-d₆) δ8.09 (s, 1H), 8.02 (s, 1H), 7.75 (s, 1H), 5.17 (q, J=7.0 Hz, 1H), 3.75(s, 3H), 3.15 (s, 3H), 3.24-3.01 (m, 3H), 2.87-2.78 (m, 2H), 2.06-1.90(m, 1H), 1.31 (d, J=7.1 Hz, 3H), 1.20 (d, J=1.1 Hz, 9H). LCMS (ES)[M+1]⁺ m/z: 357.4.

Example 1.116 Synthesis ofN-tert-butyl-2-({2-[4-(2-hydroxyethyl)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 113)

Scheme 69 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 250-mL 3-necked round-bottom flask purged and maintained in aninert atmosphere of nitrogen, was placed 2-chloro-4-methylpyridine (10.0g, 78.39 mmol, 1.0 equiv) and THE (100 mL). This was followed by theaddition of LDA (2 M in THF) (117.5 mL, 235.17 mmol, 3.0 equiv) at −78°C. After addition, the reaction solution was stirred for 2 hr at −78° C.To this, diethyl carbonate (13.9 g, 117.66 mmol, 1.50 equiv) was added.The mixture was stirred for 3 h at room temperature. The reaction wasthen quenched by the addition of NH₄Cl (aq) (200 mL) and extracted with3×100 mL of ethyl acetate. The combined organic phase was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnwith ethyl acetate/petroleum ether (4:1). This resulted in 10.0 g (64%)of ethyl 2-(2-chloropyridin-4-yl)acetate was obtained as a yellow oil.LCMS (ES) [M+1]⁺ m/z: 200.

Step 2

Into a 250-mL 3-necked round-bottom flask was placed ethyl2-(2-chloropyridin-4-yl)acetate (10.0 g, 50.09 mmol, 1.0 equiv) and EtOH(100 mL). This was followed by the addition of NaBH₄ (9.50 g, 251.10mmol, 5.0 equiv) in several batches at 0° C. After addition, the mixturewas stirred for 3 h at room temperature. The reaction was then quenchedby the addition of water (300 mL) and extracted with 3×100 mL ofdichloromethane. The combined organic phase was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. This resulted in 7.5 g (95%) of2-(2-chloropyridin-4-yl)ethan-1-ol as a yellow oil, which was used inthe next step directly without further purification. LCMS (ES) [M+1]⁺m/z: 158.

Step 3

Into a 100-mL round-bottom flask was placed2-(2-chloropyridin-4-yl)ethan-1-ol (4.78 g, 30.33 mmol, 1.0 equiv), DCM(40 mL), DHP (5.10 g, 60.63 mmol, 2.0 equiv), and TsOH (524 mg, 3.04mmol, 0.1 equiv). The reaction was stirred for 2 h at room temperature.The solution was concentrated to remove the solvent, and the residue waspurified by silica gel column with ethyl acetate/petroleum ether (1/3)to yield 2.0 g (27%) of2-chloro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridine as acolorless oil. LCMS (ES) [M+1]⁺ m/z: 242.

Step 4

Into a 50-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen was placed2-chloro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridine (800 mg,3.31 mmol, 1.0 equiv), dioxane (10.0 mL), hexamethyldistannane (1.3 g,3.97 mmol, 1.2 equiv), and Pd(PPh₃)₄ (765 mg, 0.66 mmol, 0.2 equiv). Themixture was stirred for 2 h at 100° C. After being cooled to roomtemperature, the reaction solution was used in the next step directlywithout purification. LCMS (ES) [M+1]⁺ m/z: 372.

Step 5

Into a 40-mL vial purged and maintained in an inert atmosphere ofnitrogen was placed4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2-(trimethylstannyl)pyridine(the reaction solution of last step), dioxane (10.0 mL),N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(Intermediate II, 385 mg, 1.30 mmol, 0.6 equiv), and Pd(PPh₃)₄ (500 mg,0.43 mmol, 0.2 equiv). The mixture was stirred for 12 h at 100° C. Themixture was cooled and concentrated to remove the solvent, and theresidue was purified by silica gel column with THF/PE (2/1) to yield 500mg (50%) ofN-(tert-butyl)-2-(methyl(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamideas a yellow oil. LCMS (ES) [M+1]⁺ m/z: 468.

Step 6

Into a 20-mL vial was placedN-(tert-butyl)-2-(methyl(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide(184 mg, 0.39 mmol, 1.0 equiv), methanol (5.0 mL), and para-toluenesulfonic acid (68 mg, 0.39 mmol, 1.0 equiv). The reaction solution wasstirred for 1 h at room temperature. The reaction solution was purifiedby Prep-HPLC with the following conditions: Column, Atlantis HILIC OBDColumn, 19*150 mm*5 um, mobile phase, Water (10 mmol/L) with (0.5 HCOOH)and MeOH:ACN=1:1 (33% Phase B up to 45% within 9 min), Detector, UV 254nm. This resulted in 89.2 mg (59%) ofN-(tert-butyl)-2-((2-(4-(2-hydroxyethyl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideformate as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 8.53(d, J=4.8 Hz, 1H), 8.24 (br, 1H), 8.17 (s, 1H), 7.70 (s, 1H), 7.32 (d,J=3.6 Hz, 1H), 4.16 (s, 2H), 3.70 (t, J=6.6 Hz, 2H), 3.27 (s, 3H), 3.15(t, J=7.2 Hz, 2H), 2.86-2.79 (m, 4H), 2.04-1.94 (m, 2H), 1.23 (s, 9H).LCMS (ES, m/z): [M+H]⁺: 384.2.

Example 1.117 Synthesis of(2R)—N-tert-butyl-3-methyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}butanamide(Compound 114)

Scheme 70 depicts a synthetic route for preparing an exemplary compound.

Step 1

(2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (0.50 g; 2.30mmol; 1.00 eq.) was dissolved in dichloromethane (23 ml) and cooled inan ice bath. Tert-butylamine (0.27 mL; 2.53 mmol; 1.10 eq.),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 0.96 g; 2.53 mmol; 1.10 eq.), andHunig's base (0.84 mL; 4.83 mmol; 2.10 eq.) were then added. Thereaction was stirred to 25° C. over 20 h and then taken up in ethylacetate (100 ml), water (10 ml), and sodium bicarbonate solution (50ml). The phases were separated, and the aqueous phase was extracted withmore ethyl acetate (100 ml). The combined organics were washed withsodium chloride solution (30 ml), dried over sodium sulfate, andevaporated. The residue was purified by silica gel chromatography (ethylacetate/hexanes gradient) to give tert-butylN-{1-[(1-hydroxy-3-phenylpropan-2-yl)carbamoyl]ethyl}-N-methylcarbamate(0.6 g, 96%) as a white solid.

Tert-butylN-{1-[(1-hydroxy-3-phenylpropan-2-yl)carbamoyl]ethyl}-N-methylcarbamate(0.56 g; 1.66 mmol; 1.00 eq.) was dissolved in dichloromethane (7 ml)and cooled in an ice bath. Trifluoroacetic acid (3.7 ml) was addedslowly and the reaction was stirred to 25° C. over 3 h. The reaction wasevaporated, and the residue was co-evaporated with toluene and driedunder high vacuum to give (2R)-2-amino-N-tert-butyl-3-methylbutanamide;trifluoroacetic acid, which was used directly in the next step. LCMS(ES+): (M+H)⁺=172.9.

Step 2

2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200.00 mg; 1.06mmol; 1.00 eq.) was dissolved in acetonitrile (4 ml), and to this wasadded (2R)-2-amino-N-tert-butyl-3-methylbutanamide; trifluoroacetic acid(333.18 mg; 1.16 mmol; 1.10 eq.), and Hunig's base (0.92 mL; 5.29 mmol;5.00 eq.). The mixture was stirred at 70° C. for 15 h, the solvent wasthen evaporated under reduced pressure, and the residue was purified bycolumn chromatography (50% EtOAc in Hexanes) to give(2R)—N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}amino)-3-methylbutanamide(266 mg, 77%). LCMS (ES+): (M+H)⁺=324.9. ¹H NMR (400 MHz, DMSO-d6) δ7.64 (s, 1H), 6.85 (d, J=8.3 Hz, 1H), 4.32-4.24 (m, 1H), 2.75-2.65 (m,4H), 2.09-1.96 (m, 3H), 1.25 (s, 9H), 0.92-0.86 (m, 6H).

Step 3

(2R)—N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}amino)-3-methylbutanamide(262 mg; 0.81 mmol; 1 eq.) was dissolved in N,N-dimethylformamide (15ml) and cooled in an ice bath. Sodium hydride (34 mg; 0.85 mmol; 1.05eq., 60%) was added and the mixture was stirred for 20 min. Iodomethane(53 μL; 0.85 mmol; 1.05 eq.) was then added and the reaction was stirredto 25° C. over 1.5 h. The reaction was quenched by the addition of water(90 ml) and then extracted with ethyl acetate (2×100 ml). The combinedorganic phases were washed with water (30 ml) and sodium chloridesolution (30 ml), and then dried over sodium sulfate. After evaporation,the residue was purified by silica gel chromatography (ethylacetate/hexanes gradient) to give(2R)—N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-3-methylbutanamide(255 mg, 93%) as a film. MS (ES+): (M+H)⁺=339.3.

Step 4

(2R)—N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-3-methylbutanamide(147.00 mg; 0.43 mmol; 1.00 eq.) was dissolved in 1,4-dioxane (3.5 ml),and the solution was purged with Ar gas. 2-(tributylstannyl)pyridine(0.28 mL; 0.87 mmol; 2.00 eq.) and tetrakis(triphenylphosphane)palladium (50.13 mg; 0.04 mmol; 0.10 eq.) were added The reaction vesselwas sealed and stirred in a heat bath at 110° C. for 15 h. Afterevaporation, the residue was purified by reverse phase chromatography(Waters XSelect CSH C18 column, 0-70% acetonitrile/0.1% aqueous formicacid gradient) to give(2R)—N-tert-butyl-3-methyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}butanamide(98 mg, 59%) as a light yellow solid. LCMS (ES+): (M+H)⁺=382.0. ¹H NMR(400 MHz, DMSO-d6) δ 8.72 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.41 (dt,J=8.0, 1.1 Hz, 1H), 7.98-7.89 (m, 2H), 7.52-7.46 (m, 1H), 4.56 (d,J=11.0 Hz, 1H), 3.27-3.20 (m, 1H), 3.14 (s, 3H), 3.10-3.00 (m, 1H),2.99-2.88 (m, 1H), 2.85-2.76 (m, 1H), 2.36-2.25 (m, 1H), 2.06-1.89 (m,2H), 1.18 (s, 9H), 0.95 (d, J=6.4 Hz, 3H), 0.86 (d, J=6.6 Hz, 3H).

Example 1.118 Synthesis of(2S)—N-tert-butyl-3-methyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}butanamide(Compound 115)

Compound 115 was synthesized similar to compound 114 by replacing(2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid with(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid. LCMS (ES+):(M+H)⁺=382.0. ¹H NMR (400 MHz, DMSO-d6) δ 8.73 (ddd, J=4.8, 1.8, 0.9 Hz,1H), 8.45-8.40 (m, 1H), 7.98-7.90 (m, 2H), 7.51 (ddd, J=7.5, 4.8, 1.2Hz, 1H), 4.57 (d, J=11.0 Hz, 1H), 3.28-3.21 (m, 1H), 3.16 (s, 3H),3.10-3.00 (m, 1H), 2.99-2.88 (m, 1H), 2.86-2.76 (m, 1H), 2.37-2.26 (m,1H), 2.15-1.91 (m, 2H), 1.19 (s, 9H), 0.95 (d, J=6.5 Hz, 3H), 0.86 (d,J=6.6 Hz, 3H).

Example 1.119 Synthesis of(2R)—N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-4-(methylsulfanyl)butanamide(Compound 116)

Compound 116 was synthesized similar to Compound 114 by replacing(2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid in with(2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid.LCMS (ES+): (M+H)⁺=414.0. ¹H NMR (400 MHz, DMSO-d6) δ 8.70 (ddd, J=4.7,1.8, 0.9 Hz, 1H), 8.43-8.35 (m, 1H), 7.97-7.88 (m, 2H), 7.48 (ddd,J=7.5, 4.8, 1.2 Hz, 1H), 5.11 (dd, J=8.9, 6.2 Hz, 1H), 3.26-3.17 (m,1H), 3.13-3.04 (m, 4H), 2.97-2.87 (m, 1H), 2.87-2.77 (m, 1H), 2.48-2.36(m, 2H), 2.15-1.92 (m, 7H), 1.20 (s, 9H).

Example 1.120 Synthesis of(2S)—N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-4-methylsulfanyl)butanamide(Compound 117)

Compound 117 was synthesized similar to Compound 114 by replacing(2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid in with(2S)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid.LCMS (ES+): (M+H)⁺=414.1. ¹H NMR (400 MHz, DMSO-d6) δ 8.72 (ddd, J=4.8,1.8, 0.9 Hz, 1H), 8.45-8.36 (m, 1H), 7.99-7.87 (m, 2H), 7.51 (ddd,J=7.5, 4.7, 1.2 Hz, 1H), 5.13 (dd, J=8.9, 6.1 Hz, 1H), 3.25-3.19 (m,1H), 3.15-3.05 (m, 4H), 3.00-2.78 (m, 2H), 2.48-2.37 (m, 2H), 2.16-1.93(m, 7H), 1.20 (s, 9H).

Example 1.121 Synthesis of(2R)—N-cyclohexyl-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 118)

Scheme 71 depicts a synthetic route for preparing an exemplary compound.

To a solution of(2R)-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-cyclohexylpropanamide(134.00 mg; 0.40 mmol; 1.00 eq.) and1-methyl-4-(tributylstannyl)-1H-imidazole (251.17 mg; 0.63 mmol; 2.00eq.) in Toluene (2 mL) was added tetrakis(triphenylphosphane) palladium(45.97 mg; 0.04 mmol; 0.10 eq.). The solution was heated at 105° C. for15 h, cooled to room temperature, and concentrated to remove solvent.The residue was purified by preparative HPLC to give(2R)—N-cyclohexyl-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propenamide(135 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 8.15-8.05 (m, 2H), 8.01 (d, J=8.1Hz, 1H), 5.23 (q, J=6.9 Hz, 1H), 3.76 (s, 3H), 3.52 (s, 1H), 3.15 (s,3H), 3.24-3.03 (m, 2H), 2.94-2.76 (m, 2H), 1.99 (ddt, J=20.4, 13.0, 5.5Hz, 2H), 1.72-1.62 (m, 2H), 1.62-1.54 (m, 2H), 1.51 (d, J=12.3 Hz, 1H),1.33 (d, J=7.0 Hz, 3H), 1.30-1.12 (m, 3H), 1.08 (ddd, J=19.3, 14.8, 8.6Hz, 2H). LCMS (ES, m/z): [M+H]⁺: 383.2.

Example 1.122 Synthesis of(2R)—N-cyclohexyl-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}propanamide(Compound 119)

Scheme 72 depicts a synthetic route for preparing an exemplary compound.

To a solution of(2R)-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-cyclohexylpropanamide(125.00 mg; 0.37 mmol; 1.00 eq.) and4-methoxy-2-(tributylstannyl)pyridine (251.17 mg; 0.63 mmol; 2.00 eq.)in Toluene (2 mL) was added tetrakis(triphenylphosphane) palladium(42.88 mg; 0.04 mmol; 0.10 eq.). The solution was heated at 105° C. for15 h, cooled to room temperature, and concentrated to remove solvent.The residue was purified by preparative HPLC to give(2R)—N-cyclohexyl-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}propenamide(62 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, J=5.8 Hz, 1H), 8.11 (d,J=8.0 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.16 (dd, J=5.8, 2.6 Hz, 1H),5.07 (q, J=7.0 Hz, 1H), 3.94 (s, 3H), 3.53 (d, J=6.6 Hz, 1H), 3.25-3.17(m, 1H), 3.15 (s, 3H), 3.15-3.05 (m, 1H), 2.87 (tdd, J=16.9, 13.0, 7.0Hz, 2H), 2.12-1.90 (m, 2H), 1.71 (s, 1H), 1.51 (d, J=12.2 Hz, 1H), 1.50(s, 3H), 1.34 (d, J=7.1 Hz, 3H), 1.20 (t, J=9.7 Hz, 2H), 1.16-1.06 (m,1H), 0.99 (s, 2H). LCMS (ES, m/z): [M+H]⁺: 410.1.

Example 1.123 Synthesis of(2S)-3-(tert-butoxy)-N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 120)

Compound 120 was synthesized similar to Compound 114 by replacing(2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid with(2S)-3-tert-butoxy-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoicacid. MS (ES+): (M+H)⁺=426.1. ¹H NMR (400 MHz, DMSO-d6) δ 8.68 (ddd,J=4.8, 1.8, 0.9 Hz, 1H), 8.41-8.33 (m, 1H), 7.94-7.86 (m, 1H), 7.81 (s,1H), 7.46 (ddd, J=7.5, 4.7, 1.2 Hz, 1H), 5.00 (dd, J=8.0, 5.9 Hz, 1H),3.83-3.75 (m, 1H), 3.73-3.65 (m, 1H), 3.29-3.20 (m, 2H), 3.18 (s, 3H),3.12-3.02 (m, 1H), 2.93-2.74 (m, 2H), 2.10-1.90 (m, 2H), 1.19 (s, 9H),1.14 (s, 9H).

Example 1.124 Synthesis of(2R)-3-(tert-butoxy)-N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 121)

Compound 121 was synthesized similar to Compound 114 by replacing(2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid with(2R)-3-tert-butoxy-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoicacid. MS (ES+): (M+H)⁺=426.1. ¹H NMR (400 MHz, DMSO-d6) δ 8.69 (ddd,J=4.7, 1.8, 0.9 Hz, 1H), 8.41-8.33 (m, 1H), 7.94-7.85 (m, 1H), 7.81 (s,1H), 7.46 (ddd, J=7.5, 4.7, 1.2 Hz, 1H), 5.00 (dd, J=7.9, 5.9 Hz, 1H),3.82-3.76 (m, 1H), 3.70 (dd, J=9.5, 8.0 Hz, 1H), 3.26-3.20 (m, 1H), 3.18(s, 3H), 3.12-3.02 (m, 1H), 2.93-2.75 (m, 2H), 2.10-1.90 (m, 2H), 1.19(s, 9H), 1.14 (s, 9H).

Example 1.125 Synthesis ofN-tert-butyl-2-[(2-{2H,3H-[1,4]dioxino[2,3-c]pyridin-7-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 122)

Scheme 73 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 250-mL 3-necked round-bottom flask purged and maintained in aninert atmosphere of nitrogen was placed 2-bromo-5-fluoropyridine (9.80g, 55.68 mmol, 1.00 equiv) and THF (100 mL). This was followed by theaddition of LDA (33.4 mL, 66.80 mmol, 1.20 equiv) dropwise with stirringat −78° C. The reaction solution was stirred for 0.5 hr at −78° C. Tothis was added a solution of iodine (14.13 g, 55.68 mmol, 1.00 equiv) inTHF (20 mL) dropwise with stirring at −78° C. and stirred for 1.5 hr at−78° C. The reaction was then quenched by the addition of 100 mL ofNH₄Cl (aq) and extracted with 3×50 mL of ethyl acetate. The combinedorganic layers were dried over anhydrous sodium sulfate, filtered, andthe filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column with petroleum ether/THF (10/1) to give16.0 g (95%) of 2-bromo-5-fluoro-4-iodopyridine as a white solid. LCMS(ES)[M+1]⁺ m/z: 302.

Step 2

Into a 250-mL round-bottom flask was placed2-bromo-5-fluoro-4-iodopyridine (8.0 g, 26.50 mmol, 1.00 equiv),ethylene glycol (50.0 mL), NMP (50.0 mL), and t-BuOK (5.95 g, 53.00mmol, 2.0 equiv). The reaction was stirred for 3 h at 65° C. The mixturewas cooled and diluted with 100 mL of H₂O and extracted with 3×50 mL ofethyl acetate. The combined organic layers were dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel column withpetroleum ether/THF (3/1) to yield 4.9 g (53.7%) of2-[(6-bromo-4-iodopyridin-3-yl)oxy]ethanol as an off-white solid. LCMS(ES) [M+1]⁺ m/z: 344.

Step 3

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen was placed2-[(6-bromo-4-iodopyridin-3-yl)oxy]ethanol (4.90 g, 14.24 mmol, 1.00equiv), isopropyl alcohol (50.00 mL),3,4,7,8-tetramethyl-1,10-phenanthroline (673 mg, 2.84 mmol, 0.20 equiv),tert-butoxypotassium (3.20 g, 28.49 mmol, 2.00 equiv), and copper(I)iodide (542 mg, 2.84 mmol, 0.20 equiv). The mixture was stirred for 2 hat 80° C. After being cooled to room temperature, the reaction solutionwas diluted with 50 mL of H₂O and extracted with 3×50 mL ofdichloromethane. The combined organic layers were dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel column withpetroleum ether/THF (4/1) to give 2.0 g (65%) of7-bromo-2H,3H-[1,4]dioxino[2,3-c]pyridine as a light yellow solid. LCMS(ES) [M+1]⁺ m/z: 216.

Step 4

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed7-bromo-2H,3H-[1,4]dioxino[2,3-c]pyridine (500 mg, 2.31 mmol, 1.00equiv), dioxane (8.0 mL), hexamethyldistannane (909 mg, 2.77 mmol, 1.20equiv), and Pd(PPh₃)₄ (267 mg, 0.23 mmol, 0.10 equiv). The mixture wasstirred for 2 h at 100° C. The reaction mixture was cooled and dilutedwith 10 mL of H₂O, and extracted with 3×10 mL of ethyl acetate. Thecombined organic phase was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. 600mg crude product of7-(trimethylstannyl)-2H,3H-[1,4]dioxino[2,3-c]pyridine was obtained as abrown oil and used to the next step without purification. LCMS (ES)[M+1]⁺ m/z: 302.

Step 5

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed7-(trimethylstannyl)-2H,3H-[1,4]dioxino[2,3-c]pyridine (454 mg, 1.51mmol, 1.50 equiv), dioxane (5.0 mL),N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(300 mg, 1.01 mmol, 1.00 equiv), and Pd(PPh₃)₄ (116 mg, 0.10 mmol, 0.10equiv). The mixture was stirred for 16 h at 100° C. The reaction mixturewas cooled and concentrated. The residue was purified by silica gelcolumn with dichloromethane/methanol (10/1). The collected crude productwas further purified by Prep-HPLC with the following conditions: Column,Atlantis HILIC OBD Column, 19*150 mm*5 um, Mobile phase, Water (0.05%NH₄OH) and CH₃CN (20% Phase B up to 45% in 15 min, hold 45% in 5 min),Detector, UV 254 nm. This resulted in 98.1 mg (24.4%) ofN-tert-butyl-2-[(2-[2H,3H-[1,4]dioxino[2,3-c]pyridin-7-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (s, 1H), 7.86 (s,1H), 7.69 (s, 1H), 4.40-4.36 (m, 4H), 4.10 (s, 2H), 3.26 (s, 3H), 3.12(t, J=7.5 Hz, 2H), 2.79 (t, J=7.8 Hz, 2H), 2.02-1.95 (m, 2H), 1.25 (s,9H). LCMS (ES) [M+1]⁺ m/z: 398.2.

Example 1.126 Synthesis of(2S)—N-tert-butyl-3-hydroxy-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 123)

Scheme 74 depicts a synthetic route for preparing an exemplary compound.

(2S)-3-(tert-butoxy)-N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamideand formic acid (62.5 mg; 0.13 mmol; 1 eq.) were dissolved indichloromethane (1 ml) and cooled in an ice bath. Trifluoroacetic acid(0.75 mL; 0.2 mol/L; 0.15 mmol; 1.13 eq.) (1 ml) was added and thereaction was stirred at 25° C. for 3.5 h. The solution was thenevaporated, the residue was co-evaporated with toluene and purified byreverse phase chromatography (Waters XSelect CSH C18 column, 0-90%acetonitrile/0.1% aqueous formic acid gradient) to give(2S)—N-tert-butyl-3-hydroxy-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(40 mg, 81%) as an off-white solid. LCMS (ES+): (M+H)⁺=369.9. ¹H NMR(400 MHz, DMSO-d6) δ 8.79-8.74 (m, 1H), 8.48 (d, J=7.9 Hz, 1H),8.07-7.99 (m, 1H), 7.87 (s, 1H), 7.61 (ddd, J=7.6, 4.7, 1.2 Hz, 1H),5.10 (t, J=7.3 Hz, 1H), 5.01 (s, 1H), 3.91-3.81 (m, 2H), 3.31-3.26 (m,4H), 3.17-3.10 (m, 1H), 3.02-2.87 (m, 2H), 2.15-1.96 (m, 2H), 1.20 (s,9H).

Example 1.127 Synthesis of(2R)—N-tert-butyl-3-hydroxy-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 124)

Scheme 75 depicts a synthetic route for preparing an exemplary compound.

Compound 124 was synthesized similar to compound 123 by replacing(2S)-3-(tert-butoxy)-N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propenamidewith(2R)-3-(tert-butoxy)-N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propenamide.LCMS (ES+): (M+H)⁺=370.0. ¹H NMR (400 MHz, DMSO-d6) δ 8.88-8.81 (m, 1H),8.59 (d, J=7.8 Hz, 1H), 8.19-8.12 (m, 1H), 7.89 (s, 1H), 7.76 (ddd,J=7.6, 4.8, 1.2 Hz, 1H), 5.34-5.00 (m, 2H), 3.92 (d, J=7.1 Hz, 2H), 3.45(s, 3H), 3.36-3.34 (m, 1H), 3.23-3.16 (m, 1H), 3.08-3.01 (m, 2H),2.20-2.02 (m, 2H), 1.22 (s, 9H).

Example 1.128 Synthesis ofN-tert-butyl-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 125)

Scheme 76 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen was placed 4-bromo-1-methylimidazole (500 mg,3.10 mmol, 1.00 equiv), dioxane (8.0 mL), hexamethyldistannane (1.22 g,3.72 mmol, 1.20 equiv), and Pd(PPh₃)₄ (358 mg, 0.31 mmol, 0.10 equiv).The mixture was stirred for 4 h at 100° C. The reaction mixture wascooled and concentrated. This resulted in 600 mg crude product of1-methyl-4-(trimethylstannyl)imidazole as brown oil. LCMS (ES) [M+1]⁺m/z: 247.

Step 2

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen was placedN-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide(300 mg, 1.01 mmol, 1.00 equiv), dioxane (5.0 mL),1-methyl-4-(trimethylstannyl)imidazole (371 mg, 1.51 mmol, 1.50 equiv),and Pd(PPh₃)₄ (116 mg, 0.10 mmol, 0.10 equiv). The mixture was stirredfor 20 h at 100° C. The reaction mixture was cooled and concentrated toremove the solvent. The residue was purified by silica gel column withdichloromethane/methanol (10/1). The product was further purified byPrep-HPLC with the following conditions: Column, Welch Xtimate C18,21.2*250 mm, 5 um, Mobile phase, Water (10 mmol/L NH₄HCO₃) andMeOH:CH₃CN=1:1 (25% Phase B up to 65% in 15 min); Detector, UV 254 nm.This resulted in 47.0 mg (13.5%) ofN-tert-butyl-2-[methyl[2-(1-methylimidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.73 (d, J=1.5 Hz, 1H),7.67-7.52 (m, 2H), 4.09 (s, 2H), 3.69 (s, 3H), 3.21 (s, 3H), 3.06 (t,J=7.5 Hz, 2H), 2.73 (t, J=7.8 Hz, 2H), 2.02-1.86 (m, 2H), 1.25 (s, 9H).LCMS (ES) [M+1]⁺ m/z: 343.2.

Example 1.129 Synthesis ofN-tert-butyl-2-{ethyl[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 126)

Scheme 77 depicts a synthetic route for preparing an exemplary compound.

Step 1

To a stirred solution of tert-butylamine (3.89 g, 53.186 mmol, 1.00equiv) and K₂CO₃ (7.34 g, 53.126 mmol, 1.00 equiv) in DCM (120.00 mL)was added chloroacetyl chloride (6.00 g, 53.126 mmol, 1.00 equiv)dropwise at 0° C. under an air atmosphere. The resulting mixture wasstirred for 16 h at room temperature under an air atmosphere. Thereaction was quenched with water at room temperature. The resultingmixture was extracted with CH₂Cl₂ (2×100 mL). The combined organiclayers were washed with brine (1×100 mL), dried over anhydrous Na₂SO₄,and filtered. The filtrate was concentrated under reduced pressure toafford N-tert-butyl-2-chloroacetamide (4 g, 50.32%) as a yellow solid.LCMS (ES) [M+1]⁺ m/z: 150.

Step 2

A solution of N-tert-butyl-2-chloroacetamide (4.00 g, 26.734 mmol, 1.00equiv) and ethylamine in EtOH (80 mL) was stirred for 16 h at 80° C.under an air atmosphere. The resulting mixture was concentrated underreduced pressure. The resulting mixture was diluted with water (50 mL)and extracted with DCM:MeOH=10:1 (3×100 mL). The combined organic layerswere washed with brine (1×100 mL), dried over anhydrous Na₂SO₄, andfiltered. The filtrate was concentrated under reduced pressure to yieldN-tert-butyl-2-(ethylamino)acetamide (3.3 g, 78.00%) as a yellow solid.LCMS (ES) [M+1]⁺ m/z: 159.

Step 3

A solution of 2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (3.00 g,15.870 mmol, 1.00 equiv), DIEA (6.15 g, 47.609 mmol, 3 equiv) andN-tert-butyl-2-(ethylamino)acetamide (3.01 g, 19.044 mmol, 1.20 equiv)in NMP (30.00 mL, 311.103 mmol, 19.60 equiv) was stirred for 2 h at 60°C. under an air atmosphere. The mixture was cooled to room temperature.The resulting mixture was extracted with EtOAc (3×100 mL). The combinedorganic layers were washed with brine (1×100 mL), dried over anhydrousNa₂SO₄, and filtered. The filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyeluting with PE/EtOAc (1:1) to yieldN-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](ethyl)amino)acetamide(2.2 g, 44.60%) as a white solid. LCMS (ES) [M+1]⁺ m/z: 311.

Step 4

To a solution of 2-bromo-4-methoxypyridine (453.68 mg, 2.413 mmol, 1.5equiv) and 2-tert-butyl-1,1,1-trimethyldistannane (906.82 mg, 2.654mmol, 1.65 equiv) in dioxane (2.00 mL) were added Pd(PPh₃)₄ (186 mg,0.161 mmol, 0.1 equiv). After being stirred for 2 h at 100° C. under anitrogen atmosphere, the mixture was cooled to room temperature. To theabove mixture was addedN-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](ethyl)amino)acetamide(500.00 mg, 1.609 mmol, 1.00 equiv), CsF (488.70 mg, 3.217 mmol, 2.00equiv), and Pd(PPh₃)₄ (186 mg, 0.161 mmol, 0.1 equiv) at roomtemperature. The resulting mixture was stirred for an additional 16 h at100° C. under a nitrogen atmosphere. The resulting mixture was cooledand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography eluting with PE/THF (1:1) to affordN-tert-butyl-2-[ethyl[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide(89 mg, 13%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (d,J=5.6 Hz, 1H), 7.87 (d, J=2.6 Hz, 1H), 7.68 (s, 1H), 7.16-6.82 (m, 1H),4.09 (s, 2H), 3.90 (s, 3H), 3.65 (q, J=7.0 Hz, 2H), 3.08 (t, J=7.2 Hz,2H), 2.82 (t, J=7.8 Hz, 2H), 2.23-1.92 (m, 2H), 1.23 (s, 9H), 3.65 (t,J=7.0 Hz, 3H). LCMS (ES) [M+1]⁺ m/z: 384.1.

Example 1.130 Synthesis ofN-(6-fluoropyridin-3-yl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 127)

Scheme 78 depicts a synthetic route for preparing an exemplary compound.

Step 1

To a solution of [(tert-butoxycarbonyl)(methyl)amino]acetic acid (2.00g; 10.57 mmol; 1.00 eq.) in DMF (15 mL) was added6-fluoro-3-pyridinylamine (1.18 g; 10.57 mmol; 1.00 eq.) followed byHunig's base (2.77 mL; 0.02 mol; 1.50 eq.) and HATU (4.02 g; 0.01 mol;1.00 eq.). After being stirred for 15 h at room temperature, it wasextracted with EtOAc. The organic layers were combined, dried, andconcentrated to give tert-butyl(2-((6-fluoropyridin-3-yl)amino)-2-oxoethyl)(methyl)carbamate as a crudeproduct (5.6 g). The crude product was diluted with DCM (10 mL), towhich 4N HCl in dioxane (10 mL) was added. After completion, the mixturewas concentrated and diluted with Sat. NaHCO₃. The aqueous layer wasextracted with EtOAc, the organic layers were combined, dried, andconcentrated to give2-[chloro(methyl)amino]-N-(6-fluoropyridin-3-yl)acetamide (2.5 g). LCMS(ES) [M+1]⁺ m/z: 184.

Step 2

To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine(1.00 g; 5.29 mmol; 1.00 eq.) in AcCN (15 mL) was added triethylamine(1.48 mL; 10.58 mmol; 2.00 eq.) and2-[chloro(methyl)amino]-N-(6-fluoropyridin-3-yl)acetamide (1.74 g; 7.93mmol; 1.50 eq.). After being heated at 80° C. for 15 h, it wasconcentrated and diluted with Sat. NaHCO₃, and extracted with EtOAc. Theorganic layers were combined, washed with brine, dried, and concentratedto give the crude product, which was purified by column chromatography(0 to 100% EtOAc) to give2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-fluoropyridin-3-yl)acetamide(1.78 g). LCMS (ES) [M+1]⁺ m/z: 336.0.

Step 3

To a solution of2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-fluoropyridin-3-yl)acetamide(95.00 mg; 0.28 mmol; 1.00 eq.) in Toluene (2 mL) was added2-(tributylstannyl)pyridine (156.24 mg; 0.42 mmol; 1.50 eq.) andtetrakis(triphenylphosphane) palladium (32.70 mg; 0.03 mmol; 0.10 eq.).After being heated at 105° C. overnight, HPLC indicated startingmaterial left. The mixture was concentrated and was added DMF (1 mL),additional tetrakis(triphenylphosphane) palladium (32.70 mg; 0.03 mmol;0.10 eq.), and 2-(tributylstannyl)pyridine (156.24 mg; 0.42 mmol; 1.50eq.). The mixture was heated for 5 h at 105° C. It was diluted withwater and subjected to purification by prep HPLC to giveN-tert-butyl-2-{ethyl[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(28.7 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H), 8.81 (d, J=4.9 Hz,1H), 8.47-8.40 (m, 2H), 8.19-8.10 (m, 1H), 8.05 (t, J=7.5 Hz, 1H), 7.71(dd, J=7.7, 4.8 Hz, 1H), 7.15 (dd, J=8.8, 3.2 Hz, 1H), 4.69 (s, 2H),3.54 (s, 3H), 3.04 (t, J=7.9 Hz, 2H), 2.49 (m, 2H), 2.16-2.03 (m, 2H).LCMS (ES) [M+1]⁺ m/z: 379.1.

Example 1.131 Synthesis ofN-(6-fluoropyridin-3-yl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 128)

Scheme 79 depicts a synthetic route for preparing an exemplary compound.

To a solution of2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-fluoropyridin-3-yl)acetamide(95.00 mg; 0.28 mmol; 1.00 eq.) in DMF (1 mL) was added4-methoxy-2-(tributylstannyl)pyridine (168.99 mg; 0.42 mmol; 1.50 eq.)and tetrakis(triphenylphosphane) palladium (32.70 mg; 0.03 mmol; 0.10eq.). After being heated at 110° C. overnight, the mixture was cooled toroom temperature and diluted with water and AcCN, and subjected topurification by preparative HPLC to giveN-(6-fluoropyridin-3-yl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(25.9 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.45 (d, J=5.7 Hz,1H), 8.39 (d, J=3.3 Hz, 1H), 8.12 (td, J=8.4, 7.9, 2.7 Hz, 1H), 7.77 (d,J=2.6 Hz, 1H), 7.13 (dt, J=8.8, 3.5 Hz, 1H), 7.05 (dd, J=5.7, 2.6 Hz,1H), 4.44 (s, 2H), 3.79 (s, 3H), 3.21 (t, J=7.4 Hz, 2H), 3.11 (t, J=7.3Hz, 1H), 2.85 (t, J=7.9 Hz, 3H), 2.72 (t, J=7.9 Hz, 1H), 2.04 (d, J=11.3Hz, 2H). LCMS (ES) [M+1]⁺ m/z: 409.2.

Example 1.132 Synthesis ofN-(6-fluoropyridin-3-yl)-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 129)

Scheme 80 depicts a synthetic route for preparing an exemplary compound.

To a solution of2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-fluoropyridin-3-yl)acetamide(95.00 mg; 0.28 mmol; 1.00 eq.) in DMF (1 mL) was added1-methyl-4-(tributylstannyl)-1H-imidazole (157.52 mg; 0.42 mmol; 1.50eq.) and tetrakis(triphenylphosphane) palladium (32.70 mg; 0.03 mmol;0.10 eq.). After being heated at 110° C. overnight, the mixture wascooled to room temperature and diluted with water and AcCN. The mixturewas subjected to purification by preparative HPLC to giveN-(6-fluoropyridin-3-yl)-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide.¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H), 10.76 (s, 1H), 8.47 (s, 1H),8.30 (s, 1H), 8.18 (s, 2H), 7.16 (dd, J=8.8, 3.2 Hz, 1H), 4.62 (d, J=4.0Hz, 2H), 3.75 (s, 4H), 3.19 (s, 1H), 2.91 (t, J=7.9 Hz, 2H), 2.78 (s,1H), 2.09-1.97 (m, 2H). LCMS (ES) [M+1]⁺ m/z: 382.2.

Example 1.133 Synthesis of(3R)-3-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-1-phenylpyrrolidin-2-one(Compound 130)

Scheme 81 depicts a synthetic route for preparing an exemplary compound.

Step 1

(2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid(0.50 g; 2.01 mmol; 1.00 eq.) was dissolved in DCM (20 ml). The mixturewas cooled in an ice water bath and HATU (0.84 g; 2.21 mmol; 1.10 eq.),Hunig's base (0.73 mL; 4.21 mmol; 2.10 eq.) and aniline (0.20 mL; 2.21mmol; 1.10 eq.) were added. After being stirred at 0° C. to r.t for 15h, the mixture was diluted with water and extracted with EtOAc. Thecombined organic phase was washed with brine, dried, and concentrated.The residue was purified by column chromatography (Hexanes/EtOAc=3:1) togive tert-butylN-[(1R)-3-(methylsulfanyl)-1-(phenylcarbamoyl)propyl]carbamate (0.58 g,89%) as a solid. LCMS (ES+): (M+Na)⁺=347.1.

Step 2

Tert-butylN-[(1R)-3-(methylsulfanyl)-1-(phenylcarbamoyl)propyl]carbamate (0.58 g;1.78 mmol; 1 eq.) was dissolved in iodomethane (2.66 mL; 43 mmol; 24eq.) and the solution was stirred at 25° C. After 19 h, the residue wasdried under vacuum and used directly in the next step. LCMS (ES+):(M+H)⁺=338.8.

Step 3

Tert-butylN-[(1R)-3-(dimethylsulfaniumyl)-1-(phenylcarbamoyl)propyl]carbamateiodide (0.83 g; 1.78 mmol; 1 eq.) was suspended in tetrahydrofuran (35ml) and cooled in an ice bath. Lithium bis(trimethylsilyl)azanide (1.78mL; 1 mol/L; 1.78 mmol; 1 eq.) was added dropwise slowly. After stirringat 0° C. for 3 h, ammonium chloride solution (10 ml) was added slowly.The solvent was evaporated and the remainder was taken up indichloromethane (100 ml) and sodium bicarbonate solution (50 ml). Thephases were separated, the aqueous phase was extracted withdichloromethane (2×50 ml), and the combined organic phases were driedover sodium sulfate. After evaporation, the residue was purified bysilica gel chromatography (ethyl acetate/hexanes gradient) to givetert-butyl N-[(3R)-2-oxo-1-phenylpyrrolidin-3-yl]carbamate (0.41 g, 82%)as a white solid. MS (ES+): (M+Na)⁺=299.0. ¹H NMR (400 MHz,Chloroform-d) δ 7.67-7.60 (m, 2H), 7.42-7.34 (m, 2H), 7.21-7.14 (m, 1H),5.28-5.17 (m, 1H), 4.41-4.27 (m, 1H), 3.85-3.76 (m, 2H), 2.85-2.74 (m,1H), 2.06-1.93 (m, 1H), 1.47 (s, 9H).

Step 4

Tert-butyl N-[(3R)-2-oxo-1-phenylpyrrolidin-3-yl]carbamate (0.41 g; 1.48mmol; 1 eq.) was dissolved in dichloromethane (5 ml) and cooled in anice bath. Trifluoroacetic acid (2.5 mL) was added slowly and thereaction was stirred at 25° C. After 1.5 h. the reaction was evaporated,the residue was co-evaporated with toluene and then dried under highvacuum to give (3R)-3-amino-1-phenylpyrrolidin-2-one; trifluoroaceticacid.

Step 5

2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.25 g; 1.32 mmol;1.00 eq.) was dissolved in acetonitrile (4.5 ml, dry), and to thesolution was added (3R)-3-amino-1-phenylpyrrolidin-2-one;trifluoroacetic acid (0.42 g; 1.45 mmol; 1.10 eq.) and Hunig's base(1.15 mL; 6.61 mmol; 5.00 eq.) (dry). After being stirred at ˜70° C. for20 h, the mixture was cooled and the solvent was evaporated, the residuewas purified by column chromatography (Hexanes/EtOAc=1:1) to give(3R)-3-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}amino)-1-phenylpyrrolidin-2-one(170 mg, 39%). LCMS (ES+): (M+H)⁺=342.9.

Step 6

(3R)-3-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}amino)-1-phenylpyrroiid-2-one(170.00 mg; 0.52 mmol; 1.00 eq.) was dissolved in DMF (3 ml) and cooledin an ice bath. Sodium hydride (62.04 mg; 1.55 mmol; 3.00 eq.) was addedand the mixture was stirred in an ice bath for 30 min before iodomethane(96.56 μL; 1.55 mmol; 3.00 eq.) was added. After being stirred at roomtemperature for 1.5 h, the mixture was diluted with water and extractedwith EtOAc. The combined organic phase was washed with brine, dried, andconcentrated. The residue was purified by column chromatography(Hexanes/EtOAc=1:1) to give(3R)-3-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-1-phenylpyrrolidin-2-one(161 mg, 91%). LCMS (ES+): (M+H)⁺=342.9.

Step 7

(3R)-3-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-1-phenylpyrrolidin-2-one(100.00 mg; 0.29 mmol; 1.00 eq.) was dissolved in 1,4-dioxane (2.4 ml)and purged with Ar gas. 2-(tributylstannyl)pyridine (0.19 mL; 0.58 mmol;2.00 eq.) and tetrakis(triphenylphosphane) palladium (33.71 mg; 0.03mmol; 0.10 eq.) were added and the mixture was stirred in a heat bath at108° C. for 20 h. The solvent was evaporated, the residue taken up inacetonitrile, filtered, and purified by reverse phase chromatography(Waters XSelect CSH C18 column, 0-70% acetonitrile/0.1% aqueous formicacid gradient) to give(3R)-3-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-1-phenylpyrrolidin-2-one(64 mg, 57%) as a white solid. LCMS (ES+): (M+H)⁺=386.0. ¹H NMR (400MHz, DMSO-d6) δ 8.57 (dd, J=4.8, 1.8 Hz, 1H), 8.17 (d, J=7.9 Hz, 1H),7.75-7.68 (m, 2H), 7.67-7.58 (m, 1H), 7.43-7.34 (m, 3H), 7.20-7.12 (m,1H), 5.46-5.25 (m, 1H), 4.00-3.82 (m, 2H), 3.27-3.22 (m, 5H), 2.86 (dd,J=8.7, 7.0 Hz, 2H), 2.45-2.30 (m, 2H), 2.07-1.97 (m, 2H).

Example 1.134 Synthesis of(3S)-3-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-1-phenylpyrrolidin-2-one(Compound 131)

Compound 131 was synthesized similar to compound 130 by replacing(2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid with(2S)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid.LCMS (ES+): (M+H)⁺=386.0. ¹H NMR (400 MHz, DMSO-d6) δ 8.57 (dd, J=4.9,1.8 Hz, 1H), 8.17 (d, J=7.9 Hz, 1H), 7.74-7.68 (m, 2H), 7.66-7.57 (m,1H), 7.43-7.33 (m, 3H), 7.19-7.12 (m, 1H), 5.44-5.26 (m, 1H), 3.92 (dtd,J=18.6, 9.5, 7.4 Hz, 2H), 3.26-3.21 (m, 5H), 2.86 (dd, J=8.7, 7.0 Hz,2H), 2.47-2.29 (m, 2H), 2.08-1.98 (m, 2H).

Example 1.135 Synthesis of(3R)-3-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-1-phenylpyrrolidin-2-one(Compound 132)

Scheme 82 depicts a synthetic route for preparing an exemplary compound.

(3R)-3-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-1-phenylpyrrolidin-2-one(60 mg; 0.18 mmol; 1 eq.) was dissolved in 1,4-dioxane (2 ml) and purgedwith Ar gas. 4-Methoxy-2-(tributylstannyl)pyridine (0.14 g; 0.35 mmol; 2eq.) and then tetrakis(triphenylphosphane) palladium (20 mg; 0.02 mmol;0.1 eq.) were added and the mixture was stirred in a heat bath at 108°C. for 20 h. The solvent was evaporated, the residue taken up inacetonitrile, filtered, and purified by reverse phase chromatography(Waters XSelect CSH C18 column, 0-70% acetonitrile/0.1% aqueous formicacid gradient) to give(3R)-3-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-1-phenylpyrrolidin-2-one(25 mg, 35%) as a white solid. LCMS (ES+): (M+H)⁺=415.9. ¹H NMR (400MHz, DMSO-d6) δ 8.37 (d, J=5.6 Hz, 1H), 7.72 (d, J=2.6 Hz, 1H),7.71-7.65 (m, 2H), 7.41-7.33 (m, 2H), 7.18-7.11 (m, 1H), 6.97 (dd,J=5.6, 2.6 Hz, 1H), 5.40 (s, 1H), 3.92 (dtd, J=16.7, 9.4, 7.3 Hz, 2H),3.78 (s, 3H), 3.24-3.19 (m, 5H), 2.84 (td, J=7.5, 1.6 Hz, 2H), 2.48-2.29(m, 2H), 2.06-1.97 (m, 2H).

Example 1.136 Synthesis ofN-(2-hydroxyethyl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 133)

Scheme 83 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed 2-bromo-4-methoxypyridine (500.00 mg,2.659 mmol, 1.00 equiv), hexamethyldistannane (1045.49 mg, 3.191 mmol,1.20 equiv), Pd(dppf)Cl₂ (194.58 mg, 0.266 mmol, 0.1 equiv), and dioxane(20.00 mL). The resulting solution was stirred for 4 hr at 100° C. Thesolution was cooled and then used for the next step directly. LCMS (ES)[M+1]⁺ m/z: 274.

Step 2

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen, was placed 4-methoxy-2-(tributylstannyl)pyridine(590.48 mg, 1.483 mmol, 1.00 equiv), ethyl2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetate(400.00 mg, 1.483 mmol, 1.00 equiv), Pd(dppf)Cl₂ (108.51 mg, 0.148 mmol,0.10 equiv), and dioxane (20.00 mL). The resulting solution was stirredfor 16 hr at 100° C. The reaction mixture was cooled. The resultingsolution was extracted with 3×30 mL of ethyl acetate and the organiclayers were combined, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with dichloromethane/methanol (10:1). This resulted in300 mg (59.08%) of ethylN-(2-(4-methoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinateas brown oil. LCMS (ES) [M+1]⁺ m/z: 343.

Step 3

Into a 50-mL round-bottom flask, was placed ethylN-(2-(4-methoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinate(300.00 mg, 0.876 mmol, 1.00 equiv), ethanolamine (64.22 mg, 1.051 mmol,1.20 equiv), AlCl₃ (11.68 mg, 0.088 mmol, 0.10 equiv), and toluene(20.00 mL). The resulting solution was stirred for 16 hr at 90° C. Thereaction mixture was cooled. The resulting solution was extracted with3×30 mL of ethyl acetate and the organic layers were combined, driedover anhydrous sodium sulfate, and concentrated under vacuum. The crudeproduct was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, Atlantis HILIC OBD Column, 19*150 mm*5 um;mobile phase, Water (0.05% NH₃H₂O) and ACN (5% PhaseB up to 18% in 8min). This resulted in 47.2 mg (15.07%) ofN-(2-hydroxyethyl)-2-((2-(4-methoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (d, J=5.7 Hz, 1H),8.14 (t, J=5.7 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H), 7.04 (dd, J=5.6, 2.6 Hz,1H), 4.65 (s, 1H), 4.20 (s, 2H), 3.90 (s, 3H), 3.44-3.35 (m, 2H), 3.28(s, 3H), 3.21-3.11 (m, 4H), 2.83 (t, J=7.8 Hz, 2H), 2.01-1.96 (m, 2H).LCMS (ES) [M+1]⁺ m/z: 358.2.

Example 1.137 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(oxan-4-yl)acetamide(Compound 134)

Scheme 84 depicts a synthetic route for preparing an exemplary compound.

To a stirred solution of[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]aceticacid (200 mg, 0.63 mmol, 1.0 equiv), DIEA (411 mg, 3.18 mmol, 5.0equiv), and HATU (1.21 g, 3.181 mmol, 5.0 equiv) in THE (10 mL) wasadded oxan-4-amine (321 mg, 3.18 mmol, 5.0 equiv) in portions at 20° C.The resulting mixture was stirred for 5 h at 60° C. The reaction wasconcentrated under reduced pressure. The residue was purified byFlash-Prep-HPLC with the following conditions (IntelFlash-1): Column,C18; mobile phase, Mobile phase: MeCN=5/1B: Water Flow rate: 20 mL/minColumn: DAICEL CHIRALPAK IC, 250*20 mm, 220 nm Gradient: 50% B in 20min; 220 nm. This resulted in 47 mg (18.5%)2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-N-(oxan-4-yl)acetamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (d, J=5.7 Hz, 1H),8.13 (d, J=7.5 Hz, 1H), 7.81 (d, J=2.4 Hz, 1H), 7.05 (dd, J=2.4 Hz, 5.7Hz, 1H), 4.18 (s, 2H), 3.89 (s, 3H), 3.81-3.77 (m, 3H), 3.31-3.28 (m,2H), 3.18-3.16 (m, 3H), 3.15 (t, J=7.2 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H),2.04-1.94 (m, 2H), 1.67-1.63 (m, 2H), 1.47-1.39 (m, 2H). LCMS (ES)[M+1]⁺ m/z: 398.2.

Example 1.138 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(oxolan-3-yl)acetamide(Compound 135)

Scheme 85 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 250-mL 3-necked round-bottom flask purged and maintained in aninert atmosphere of nitrogen was placed 2-bromo-4-methoxypyridine (7.0g, 37.22 mmol, 1.0 equiv) and toluene (70.0 mL). This was followed bythe addition of n-BuLi (16.4 mL, 41.0 mmol, 1.10 equiv) and i-PrMgBr(22.3 mL, 22.30 mmol, 0.60 equiv) dropwise with stirring at −78° C.After addition, the resulting solution was stirred for 2 hr at −78° C.To the mixture tributyltin chloride (14.54 g, 44.68 mmol, 1.20 equiv)was added at −78° C. The reaction was stirred for 1 h at roomtemperature. The reaction was then quenched by the addition of 200 mL ofNH₄Cl (aq), and extracted with 3×100 mL of toluene. The combined organicphase was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. 16.0 g crude productof 4-methoxy-2-(tributylstannyl)pyridine was obtained as a brown oil andused in the next step without purification. LCMS (ES) [M+1]⁺ m/z: 400.

Step 2

Into a 250-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen was placed ethyl2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetate(7.0 g, 25.95 mmol, 1.00 equiv), toluene (100.0 mL),4-methoxy-2-(tributylstannyl)pyridine (15.5 g, 38.92 mmol, 1.50 equiv),and Pd(PPh₃)₄ (3.0 g, 2.59 mmol, 0.10 equiv). The mixture was stirredfor 16 h at 100° C. The reaction mixture was cooled and concentrated toremove the solvent. The residue was purified by silica gel column withdichloromethane/methanol (10/1). This resulted in 3.5 g (39%) of ethyl2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetateas a brown oil. LCMS (ES) [M+1]⁺ m/z: 343.

Step 3

Into a 100-mL round-bottom flask, was placed ethyl2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetate(3.5 g, 10.22 mmol, 1.00 equiv), THF (30.0 mL), H₂O (10.0 mL), and LiOHH₂O (857 mg, 20.44 mmol, 2.00 equiv). The reaction solution was stirredfor 16 h at room temperature. The solids were collected by filtrationand dried under an infrared lamp. 2.5 g (77%) ofN-(2-(4-methoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinewas obtained as a yellow solid. LCMS (ES)[M+1]⁺ m/z: 315.

Step 4

Into a 50-mL round-bottom flask, was placedN-(2-(4-methoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycine(200 mg, 0.63 mmol, 1.00 equiv), THF (5.0 mL), oxolan-3-amine (83 mg,0.95 mmol, 1.50 equiv), DIEA (246 mg, 1.90 mmol, 3.00 equiv), and HATU(362 mg, 0.95 mmol, 1.50 equiv). The mixture was stirred for 4 h at 50°C. The reaction mixture was cooled and concentrated to remove thesolvent. The residue was diluted with 5 mL of MeOH and purified byPrep-HPLC with the following conditions: Column, Welch Xtimate C18,21.2*250 mm, 5 um, Mobile phase, Water (10 mmol/L NH₄HCO₃) andMeOH:CH₃CN=1:1 (25% Phase B up to 65% in 15 min), Detector, UV 254 nm.This resulted in 30 mg (12%) of2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-N-(oxolan-3-yl)acetamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.47 (d, J=5.7 Hz, 1H),8.35 (d, J=6.9 Hz, 1H), 7.80 (d, J=2.7 Hz, 1H), 7.03 (dd, J=5.7, 2.7 Hz,1H), 4.33-4.22 (m, 1H), 4.18 (d, J=2.4 Hz, 2H), 3.89 (s, 3H), 3.80-3.67(m, 2H), 3.70-3.57 (m, 1H), 3.43 (dd, J=8.7, 3.9 Hz, 1H), 3.27 (s, 3H),3.16 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.13-1.91 (m, 3H),1.77-1.67 (m, 1H). LCMS (ES)[M+1]⁺ m/z: 384.1.

Example 1.139 Synthesis ofN-(1-hydroxy-2-methylpropan-2-yl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 136)

Scheme 86 depicts a synthetic route for preparing an exemplary compound.

Into a 100-mL round-bottom flask was placedN-(2-(4-methoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycine(150.00 mg, 0.477 mmol, 1.00 equiv), 2-amino-2-methyl-1-propanol (85.07mg, 0.954 mmol, 2.00 equiv), HATU (272.16 mg, 0.716 mmol, 1.50 equiv),DIEA (185.02 mg, 1.432 mmol, 3.00 equiv), and DCM (20.00 mL). Theresulting solution was stirred for 6 hr at room temperature. Theresulting solution was extracted with 3×20 mL of dichloromethane and theorganic layers were combined, dried over anhydrous sodium sulfate, andconcentrated. The crude product was purified by Prep-HPLC with thefollowing conditions (2 #SHIMADZU (HPLC-01)): Column, Atlantis HILIC OBDColumn, 19*150 mm*5 um; mobile phase, Water (0.05% NH₃H₂O) and ACN (5%PhaseB up to 18% in 8 min). This resulted in 66.9 mg (36.37%) ofN-(1-hydroxy-2-methylpropan-2-yl)-2-((2-(4-methoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (d, J=6.1 Hz, 1H),8.04 (d, J=2.7 Hz, 1H), 7.69 (s, 1H), 7.44 (dd, J=6.1, 2.6 Hz, 1H), 4.88(br, 1H), 4.35 (s, 2H), 4.06 (s, 3H), 3.52-3.41 (s, 3H), 3.39-3.25 (m,2H), 3.22-3.17 (m, 2H), 3.01 (t, J=7.9 Hz, 2H), 2.15-1.99 (m, 2H), 1.17(s, 6H). LCMS (ES) [M+1]⁺ m/z: 386.2.

Example 1.140 Synthesis ofN-cyclohexyl-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 137)

Scheme 87 depicts a synthetic route for preparing an exemplary compound.

Into a 50-mL round-bottom flask, was placed[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]aceticacid (100.00 mg, 0.318 mmol, 1.00 equiv), dimethylformamide (4 mL),cyclohexylamine (31.55 mg, 0.318 mmol, 1.00 equiv), HATU (181.44 mg,0.477 mmol, 1.50 equiv), and DIEA (123.35 mg, 0.954 mmol, 3.00 equiv).The resulting solution was stirred for 2 hr at 25° C. The crude reactionmixture was filtered and subjected to reverse phase preparative HPLC(Prep-C18, 20-45 uM, 120 g, Tianjin Bonna-Agela Technologies; gradientelution of 25% MeCN in water to 35% MeCN in water over a 10 min period,water contains 0.1% NH₃H₂O) to provideN-cyclohexyl-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamideas a white solid (65 mg, 51.66%). ¹H NMR (300 MHz, DMSO-d6) δ 8.48 (d,J=5.6 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H), 7.04 (dd,J=5.6, 2.7 Hz, 1H), 4.16 (s, 2H), 3.89 (s, 3H), 3.54 (s, 1H), 3.26 (s,3H), 3.14 (t, J=7.2 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 1.89-2.07 (m, 2H),1.81-1.45 (m, 5H), 1.12-1.32 (m, 5H). LCMS (ES) [M+1]⁺ m/z 396.2.

Example 1.141 Synthesis ofN-(3-fluorophenyl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 138)

Scheme 88 depicts a synthetic route for preparing an exemplary compound.

Into a 50-mL round-bottom flask, was placed[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]aceticacid (100.00 mg, 0.318 mmol, 1.00 equiv), dimethylformamide (4 mL),3-fluoroaniline (35.35 mg, 0.318 mmol, 1.00 equiv), HATU (181.44 mg,0.477 mmol, 1.50 equiv), and DIEA (123.35 mg, 0.954 mmol, 3.00 equiv).The resulting solution was stirred for 2 hr at 25° C. The crude reactionmixture was filtered and subjected to reverse phase preparative HPLC(Prep-C18, 20-45 uM, 120 g, Tianjin Bonna-Agela Technologies; gradientelution of 25% MeCN in water to 35% MeCN in water over a 10 min period,water contains 0.1% NH₃H₂O) to provideN-(3-fluorophenyl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamideas a white solid (62 mg, 47.83%). ¹H NMR (300 MHz, DMSO-d6) δ 10.43 (s,1H), 8.44 (d, J=5.6 Hz, 1H), 7.77 (d, J=2.6 Hz, 1H), 7.57 (d, J=11.5 Hz,1H), 7.40-7.28 (m, 2H), 6.99 (dd, J=5.6, 2.6 Hz, 1H), 6.86-6.92 (m, 1H),4.43 (s, 2H), 3.76 (s, 3H), 3.37 (s, 3H), 3.21 (t, J=7.4 Hz, 2H), 2.84(t, J=7.8 Hz, 2H), 1.94-2.09 (m, 2H). LCMS (ES) [M+1]⁺ m/z 408.2.

Example 1.142 Synthesis ofN-(1-methoxy-2-methylpropan-2-yl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 139)

Scheme 89 depicts a synthetic route for preparing an exemplary compound.

Into a 100-mL round-bottom flask, was placedN-(2-(4-methoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycine(150.00 mg, 0.493 mmol, 1.00 equiv), 1-methoxy-tert-butylamine (76.27mg, 0.739 mmol, 1.5 equiv), HATU (281.10 mg, 0.739 mmol, 1.5 equiv),DIEA (191.09 mg, 1.479 mmol, 3 equiv), and THE (20.00 mL). The resultingsolution was stirred for 4 hr at room temperature. The resultingsolution was extracted with 3×20 mL of ethyl acetate and the organiclayers were combined, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The crude product was purified by Prep-HPLCwith the following conditions (2 #SHIMADZU (HPLC-01)): Column, WelchXtimate C18, 21.2*250 mm, 5 um; mobile phase, Water (0.05% FA) andMeOH:ACN=1:1 (10% PhaseB up to 60% in 17 min. This resulted in 55.8 mg(29.07%) ofN-(1-hydroxy-2-methylpropan-2-yl)-2-((2-(4-methoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (d, J=5.6 Hz,1H), 7.85 (d, J=2.5 Hz, 1H), 7.57 (s, 1H), 7.04 (dd, J=5.6, 2.6 Hz, 1H),4.17 (s, 2H), 3.90 (s, 3H), 3.34 (s, 2H), 3.25 (s, 3H), 3.18 (s, 3H),3.14 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.9 Hz, 2H), 2.09-1.92 (m, 2H), 1.19(s, 6H). LCMS (ES) [M+1]⁺ m/z: 400.2.

Example 1.143 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(oxan-4-yl)acetamide(Compound 140)

Scheme 90 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 50-mL round-bottom flask was placed[methyl(2-[4-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]aceticacid (200 mg, 0.46 mmol, 1.00 equiv), THE (5 mL), HATU (266 mg, 0.70mmol, 1.50 equiv), DIEA (180 mg, 1.40 mmol, 3.00 equiv), andoxan-4-amine (70 mg, 0.70 mmol, 1.50 equiv). The resulting solution wasstirred for 3 hr at 60° C. The reaction was then quenched by theaddition of 50 mL of water. The resulting solution was extracted with3×100 mL of ethyl acetate and the organic layers were combined, washedwith 3×100 ml of brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. This resulted in 90 mg (37.69%) of2-[methyl(2-[4-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]-N-(oxan-4-yl)acetamideas a yellow oil. LCMS (ES) [M+1]⁺ m/z 512.

Step 2

Into a 50-mL round-bottom flask, was placed2-[methyl(2-[4-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]-N-(oxan-4-yl)acetamide(90 mg, 0.17 mmol, 1.00 equiv), MeOH (3 mL), and TsOH (15 mg, 0.08 mmol,0.5 equiv). The resulting solution was stirred for 2 hr at 25° C. Thecrude product was purified by Prep-HPLC with the following conditions(Waters I): Column, Xbridge Prep C18 OBD column, 5 um, 19*150 mm; mobilephase, Water (0.1% FA) and CH₃CN (30% CH₃CN up to 42% in 15 min);Detector, UV 254 nm. This resulted in 38.6 mg (51.33%) of2-([2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(oxan-4-yl)acetamideas a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.47 (d, J=5.6 Hz, 1H),8.29-8.05 (m, 2H), 7.81 (d, J=2.6 Hz, 1H), 7.05 (dd, J=5.7, 2.6 Hz, 1H),4.24-4.09 (m, 4H), 3.84-3.72 (m, 5H), 3.36-3.30 (m, 2H), 3.28 (s, 3H),3.15 (t, J=7.2 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.00 (q, J=7.6 Hz, 2H),1.67 (d, J=11.3 Hz, 2H), 1.49-1.37 (m, 2H). LCMS (ES) [M+1]⁺ m/z 428.2.

Example 1.144 Synthesis ofN-[(1R,2R)-2-hydroxycyclohexyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 141)

Scheme 91 depicts a synthetic route for preparing an exemplary compound.

Into a 100-mL round-bottom flask, was placedN-(2-(4-methoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycine(150.00 mg, 0.477 mmol, 1.00 equiv), 2-aminocyclohexan-1-ol (82.44 mg,0.716 mmol, 1.50 equiv), HATU (272.16 mg, 0.716 mmol, 1.5 equiv), DIEA(185.02 mg, 1.432 mmol, 3 equiv), and DCM (20.00 mL). The resultingsolution was stirred for 4 hr at 4° C. The resulting solution wasextracted with 3×20 mL of dichloromethane and the organic layers werecombined, dried in an oven under reduced pressure, and concentratedunder vacuum. The crude product was purified by Prep-HPLC with thefollowing conditions (2 #SHIMADZU (HPLC-01)): Column, Atlantis HILIC OBDColumn, 19*150 mm*5 um; mobile phase, Water (0.05% NNH₃H₂O) and ACN (5%PhaseB up to 18% in 8 min). This resulted in 95.2 mg (48.48%) ofN-((1R,2R)-2-hydroxycyclohexyl)-2-((2-(4-methoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (d, J=5.6 Hz, 1H),7.91 (d, J=8.1 Hz, 1H), 7.82 (d, J=2.6 Hz, 1H), 7.04 (dd, J=5.7, 2.6 Hz,1H), 4.54 (d, J=4.8 Hz, 1H), 4.25 (d, J=16.4 Hz, 1H), 4.15 (d, J=16.3Hz, 1H), 3.89 (s, 3H), 3.48-3.36 (m, 1H), 3.31-3.22 (m, 4H), 3.14 (t,J=4.7 Hz, 2H), 2.82 (t, J=7.9 Hz, 2H), 2.03-1.93 (m, 2H), 1.86-1.49 (m,4H), 1.32-1.05 (m, 4H). LCMS (ES) [M+1]⁺ m/z: 412.3.

Example 1.145 Synthesis ofN-cyclohexyl-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 142)

Scheme 92 depicts a synthetic route for preparing an exemplary compound.

Into a 20-mL vial, was placed[methyl[2-(1-methylimidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]aceticacid hydrochloride (150 mg, 0.46 mmol, 1.00 equiv), DMF (3.0 mL),cyclohexylamine (51 mg, 0.51 mmol, 1.10 equiv), and DIEA (240 mg, 1.85mmol, 4.00 equiv). This was followed by the addition of HATU (264 mg,0.69 mmol, 1.50 equiv) at 0° C. The reaction solution was stirred for 2h at room temperature. The crude product was purified by Flash-Prep-HPLCwith the following conditions: Column, C18-120 g, CH₃CN/H₂O (0.05%NH₄OH) from 10% to 80% within 12 min, flow rate, 70 ml/min, Detector, UV254 nm. 83.8 mg (49%) ofN-cyclohexyl-2-[methyl[2-(1-methylimidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamidewas obtained as a white solid. ¹HNMR (300 MHz, DMSO-d₆, ppm): δ 7.95 (d,J=8.1 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.60 (d, J=1.5 Hz, 1H), 4.12 (s,2H), 3.69 (s, 3H), 3.57-3.53 (m, 1H), 3.21 (s, 3H), 3.06 (t, J=7.5 Hz,2H), 2.73 (t, J=7.8 Hz, 2H), 1.99-1.89 (m, 2H), 1.68 (t, J=10.8 Hz, 4H),1.54 (d, J=12.3 Hz, 1H), 1.27-1.07 (m, 5H). LCMS (ES, m/z): [M+H]⁺:369.2.

Example 1.146 Synthesis ofN-(1-hydroxy-2-methylpropan-2-yl)-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 143)

Scheme 93 depicts a synthetic route for preparing an exemplary compound.

Into a 20-mL vial, was placed[methyl[2-(1-methylimidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]aceticacid hydrochloride (150 mg, 0.46 mmol, 1.00 equiv), DMF (3.00 mL),2-amino-2-methyl-1-propanol (45 mg, 0.51 mmol, 1.10 equiv), and DIEA(240 mg, 1.85 mmol, 4.00 equiv). This was followed by the addition ofHATU (264 mg, 0.69 mmol, 1.50 equiv) at 0° C. The resulting solution wasstirred for 2 h at room temperature. The crude product was purified byFlash-Prep-HPLC with the following conditions: Column, C18-120 g,CH₃CN/H₂O (0.05% NH₄OH) from 10% to 80% within 12 min, flow rate, 70ml/min, Detector, UV 254 nm. 102.8 mg (62%) ofN-(1-hydroxy-2-methylpropan-2-yl)-2-[methyl[2-(1-methylimidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamidewas obtained as a white solid. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 7.74(d, J=1.5 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.46 (s, 1H), 4.93 (br, 1H),4.10 (s, 2H), 3.69 (s, 3H), 3.37 (d, J=3.9 Hz, 2H), 3.21 (s, 3H), 3.07(t, J=7.5 Hz, 2H), 2.73 (t, J=7.8 Hz, 2H), 1.99-1.89 (m, 2H), 1.18 (s,6H). LCMS (ES, m/z): [M+H]⁺: 359.2.

Example 1.147 Synthesis ofN-cyclohexyl-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 144)

Scheme 94 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 100-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen was placed a mixture of4-[2-(oxan-2-yloxy)ethoxy]-2-(trimethylstannyl)pyridine (2.00 g, 5.18mmol, 1.00 equiv), dioxane (40.0 mL, 454 mmol), ethylN-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinate(1.40 g, 5.180 mmol, 1.00 equiv), and Pd(PPh₃)₄ (598 mg, 0.518 mmol,0.10 equiv). The resulting solution was stirred for 16 hours at 100° C.After cooling, the solution was concentrated. The residue was appliedonto a silica gel column eluting with dichloromethane/methanol (10/1).This resulted in 826 mg (34.93%) of ethylN-methyl-N-(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycinateas a brown crude oil. LCMS (ES) [M+1]⁺ m/z: 457.

Step 2

Into a 20-mL vial was placed a mixture of ethylN-methyl-N-(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycinate(800 mg, 1.75 mmol, 1.00 equiv), MeOH (8.00 mL), H₂O (2.00 mL), and LiOH(83.9 mg, 3.50 mmol, 2.00 equiv). The resulting solution was stirred for2 hours at room temperature. The crude reaction mixture was filtered andsubjected to reverse phase preparative MPLC (Prep-C18, 20-45 mM, 120 g,Tianjin Bonna-Agela Technologies; gradient elution of 5% MeCN in waterto 27% MeCN in water over a 12 min period, where both solvents contain0.1% NH₃H₂O). This resulted in 568 mg (75.65%) ofN-methyl-N-(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycineas a red solid. LCMS (ES) [M+1]⁺ m/z: 429.

Step 3

Into an 8-mL vial, was placedN-methyl-N-(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycine(150 mg, 0.350 mmol, 1.00 equiv), DMF (2.00 mL), cyclohexylamine (34.7mg, 0.350 mmol, 1.00 equiv), DIEA (135 mg, 1.05 mmol, 3.00 equiv) andHATU (159 mg, 0.420 mmol, 1.20 equiv). The resulting solution wasstirred for 3 hours at room temperature. The crude reaction mixture wasfiltered and the filtrate was subjected to reverse phase preparativeMPLC (Prep-C18, 20-45 mM, 120 g, Tianjin Bonna-Agela Technologies;gradient elution of 8% MeCN in water to 33% MeCN in water over a 12 minperiod, where both solvents contain 0.1% NH₃H₂O). This resulted in 126mg (70.62%) ofN-cyclohexyl-2-(methyl(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamideas a brown oil. LCMS (ES) [M+1]⁺ m/z: 510.

Step 4

Into an 8-mL vial was placed a mixture ofN-cyclohexyl-2-(methyl(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide(120 mg, 0.235 mmol, 1.00 equiv), MeOH (3.00 mL), and TsOH (20.2 mg,0.118 mmol, 0.50 equiv). The resulting solution was stirred for 2 hoursat room temperature. The crude product was purified by Prep-HPLC withthe following conditions: SunFire Prep C18 OBD Column, 19×150 mm, 5 um;mobile phase, phase A: H₂O (0.1% FA); phase B: CH₃CN (5% CH₃CN up to 20%CH₃CN in 8 min). This resulted in 22.5 mg (22.46%) ofN-cyclohexyl-2-((2-(4-(2-hydroxyethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas an off-white solid. ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 8.55 (d, J=5.9Hz, 1H), 8.14 (s, OH), 8.03 (d, J=7.9 Hz, 1H), 7.89 (d, J=2.6 Hz, 1H),7.22 (dd, J=5.9, 2.6 Hz, 1H), 4.96 (br, 1H), 4.24-4.20 (m, 4H),3.77-3.68 (m, 2H), 3.62-3.47 (m, 1H), 3.33 (s, 3H), 3.18 (t, J=7.3 Hz,2H), 2.89 (t, J=7.8 Hz, 2H), 2.07-1.97 (m, 2H), 1.72-1.52 (m, 5H),1.31-1.07 (m, 5H). LCMS (ES) [M+1]⁺ m/z: 426.2.

Example 1.148 Synthesis ofN-tert-butyl-2-{[2-(4,5-dimethoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 145)

Scheme 95 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 25-mL round-bottom flask was placed a solution of6-bromopyridin-3-ol (800.00 mg, 4.598 mmol, 1.00 equiv) in DMF (10 mL),methyl iodide (717.86 mg, 5.058 mmol, 1.10 equiv), and K₂CO₃ (762.53 mg,5.517 mmol, 1.2 equiv). The resulting solution was stirred for 12 hr atroom temperature. The resulting solution was diluted with 50 mL of H₂O,extracted with 2×50 mL of ethyl acetate, the organic layers werecombined, dried over anhydrous sodium sulfate, and concentrated. Thisresulted in 780 mg (90.23%) of 2-bromo-5-methoxypyridine as a lightyellow oil. LCMS (ES) [M+1]⁺ m/z: 188.

Step 2

Into a 25-mL round-bottom flask, was placed a solution of2-bromo-5-methoxypyridine (700.00 mg, 3.723 mmol, 1.00 equiv) in DCM (15mL), and mCPBA (770.94 mg, 4.468 mmol, 1.2 equiv). The resultingsolution was stirred for 10 hr at room temperature. The reaction wasthen quenched by the addition of 20 mL of water/ice. The resultingsolution was extracted with 2×20 mL of dichloromethane. The combinedorganic layers were washed with 3×20 mL of aq Na₂SO₃, dried overanhydrous sodium sulfate, and concentrated. The residue was applied ontoa silica gel column with ethyl acetate/petroleum ether (1:2). Thisresulted in 550 mg (72.41%) of 2-bromo-5-methoxypyridine 1-oxide as alight yellow solid. LCMS (ES) [M+1]⁺ m/z: 204.

Step 3

Into a 50-mL round-bottom flask, was placed H₂SO₄ (12.00 mL),2-bromo-5-methoxypyridine 1-oxide (500.00 mg, 2.451 mmol, 1.00 equiv).This was followed by the addition of HNO₃ (8.00 mL, 0.127 mmol, 0.05equiv) dropwise with stirring at 0° C. in 30 min. The resulting solutionwas stirred for 30 min at 0° C. in an ice/salt bath. The resultingsolution was stirred for an additional 12 hr while the temperature wasmaintained at 100° C. in an oil bath. The resulting solution was dilutedwith 100 mL of ice water. The pH value of the solution was adjusted to10 with NaOH (5 mol/L). The resulting mixture was extracted with 3×30 mLof ethyl acetate, and the combined organic layers were dried andconcentrated. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:1). This resulted in 220 mg of2-bromo-5-methoxy-4-nitropyridine as a light yellow solid. LCMS (ES)[M+1]⁺ m/z: 233.

Step 4

Into a 20-mL round-bottom flask was placed a solution of2-bromo-5-methoxy-4-nitropyridine (200.00 mg, 0.858 mmol, 1.00 equiv) inMeOH (5 mL) and sodium methoxide (69.55 mg, 1.287 mmol, 1.50 equiv). Theresulting solution was stirred for 3 hr at room temperature. Theresulting solution was diluted with 20 mL of H₂O, extracted with 2×20 mLof dichloromethane. The combined organic layers were dried overanhydrous sodium sulfate and concentrated. This resulted in 110 mg(58.78%) of 2-bromo-4,5-dimethoxypyridine as an off-white solid. LCMS(ES) [M+1]⁺ m/z: 218.

Step 5

Into a 25-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen was placed a solution of2-bromo-4,5-dimethoxypyridine (300.00 mg, 1.376 mmol, 1.00 equiv) in Tol(mL), Sn₂Me₆ (450.76 mg, 1.376 mmol, 1.00 equiv), and Pd(dppf)Cl₂(1006.70 mg, 1.376 mmol, 1 equiv). The resulting solution was stirredfor 3 hr at 100° C. in an oil bath. The resulting solution was dilutedwith 20 mL of H₂O, extracted with 2×20 mL of ethyl acetate. The combinedorganic layers were dried over anhydrous sodium sulfate and concentratedunder vacuum. This resulted in 220 mg (37.34%) of4,5-dimethoxy-2-(tributylstannyl)pyridine as a brown solid. LCMS (ES)[M+1]⁺ m/z: 430.

Step 6

Into a 20-mL round-bottom flask purged and maintained in an inertatmosphere of nitrogen was placed a solution of4,5-dimethoxy-2-(tributylstannyl)pyridine (220.00 mg, 0.514 mmol, 1.00equiv) in Tol (6 mL), tert-butyl2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetate(152.99 mg, 0.514 mmol, 1 equiv), and Pd(dppf)Cl₂ (37.59 mg, 0.051 mmol,0.10 equiv). The resulting solution was stirred for 12 hr at 100° C. inan oil bath. The resulting mixture was concentrated. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:1). The collected fractions were combined and concentrated. The crudeproduct was purified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column C18; mobile phase, ACN:H₂O (0.01% TFA)=1:20increasing to ACN:H₂O (0.01% TFA)=1:5 within 15 min; Detector, UV 254nm. This resulted in 80 mg (38.98%) ofN-(tert-butyl)-2-((2-(4,5-dimethoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a white solid. H NMR (300 MHz, DMSO-d₆) δ 8.24 (s, 1H), 7.92 (s, 1H),7.64 (s, 1H), 4.16 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.25 (s, 3H),3.13 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.03-1.95 (m, 2H), 1.22(s, 9H). LCMS (ES) [M+1]⁺ m/z: 400.2.

Example 1.149 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(3-methyloxolan-3-yl)acetamide(Compound 146)

Scheme 96 depicts a synthetic route for preparing an exemplary compound.

Step 1

To a solution of [(tert-butoxycarbonyl)(methyl)amino]acetic acid (1.00g; 5.29 mmol; 1.00 eq.) in DMF (15 mL) was added 3-methyloxolan-3-amine(0.53 g; 5.29 mmol; 1.00 eq.), followed by Hunig's base (1.38 mL; 0.01mol; 1.50 eq.) and HATU (2.01 g; 0.01 mol; 1.00 eq.). After beingstirred for 15 h at room temperature, the mixture was extracted withEtOAc, the organic layers were combined, dried, and concentrated to givedesired crude product. The crude product was diluted with DCM (10 mL),to which was added 4N HCl in dioxane (10 mL). After completion, themixture was concentrated and diluted with Sat. NaHCO₃. The aqueous layerwas extracted with EtOAc, and then the organic layers were combined andconcentrated to give2-[chloro(methyl)amino]-N-(3-methyloxolan-3-yl)acetamide (2.80 g). LCMS(ES) [M+1]⁺ m/z: 173.4.

Step 2

To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.66 g; 3.50 mmol; 1.00 eq.) in AcCN (10 mL) was added2-[chloro(methyl)amino]-N-(3-methyloxolan-3-yl)acetamide (1.10 g; 5.25mmol; 1.50 eq.) and triethylamine (1.96 mL; 14.00 mmol; 4.00 eq.). Afterbeing stirred at 80° C. for 15 h, the mixture was cooled to roomtemperature and concentrated to remove solvent. The residue was purifiedby column chromatography (DCM/MeOH=10:1) to give2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(3-methyloxolan-3-yl)acetamide.LCMS (ES) [M+1]⁺ m/z: 325.1, 327.2.

Step 3

To a solution of 4-methoxy-2-(tributylstannyl)pyridine (183.88 mg; 0.46mmol; 1.50 eq.) and2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(3-methyloxolan-3-yl)acetamide(100.00 mg; 0.31 mmol; 1.00 eq.) in Toluene (1.0 mL) was addedtetrakis(triphenylphosphane) palladium (35.58 mg; 0.03 mmol; 0.10 eq.).The mixture was degassed and heated at 105° C. for 15 h. HPLC indicatedslow conversion. The mixture was concentrated and was added DMF (1 mL)more 4-methoxy-2-(tributylstannyl)pyridine (183.88 mg; 0.46 mmol; 1.50eq.) and tetrakis(triphenylphosphane) palladium (35.58 mg; 0.03 mmol;0.10 eq.). The mixture was heated further for 15 hr at 100° C., cooled.and diluted with water and AcCN and was subjected to purification bypreparative HPLC to giveN-tert-butyl-2-{ethyl[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(16 mg). ¹H NMR (400 MHz, Methanol-d₄) δ 8.62 (d, J=6.1 Hz, 1H), 8.06(d, J=2.6 Hz, 1H), 7.35 (dd, J=6.1, 2.7 Hz, 1H), 4.49-4.33 (m, 2H), 4.07(s, 3H), 3.96 (dd, J=13.9, 8.8 Hz, 1H), 3.94-3.81 (m, 2H), 3.61 (t,J=8.3 Hz, 1H), 3.51 (s, 3H), 3.33 (d, J=7.3 Hz, 2H), 3.13-2.94 (m, 2H),2.30 (dq, J=13.3, 6.7 Hz, 1H), 2.26-2.13 (m, 2H), 2.07-1.86 (m, 1H),1.45 (d, J=15.2 Hz, 3H). LCMS (ES) [M+1]⁺ m/z: 398.0.

Example 1.150 Synthesis of2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(3-methyloxolan-3-yl)acetamide(Compound 147)

Scheme 97 depicts a synthetic route for preparing an exemplary compound.

To a solution of 1-methyl-4-(tributylstannyl)-1H-imidazole (171.40 mg;0.46 mmol; 1.50 eq.) and2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(3-methyloxolan-3-yl)acetamide(100.00 mg; 0.31 mmol; 1.00 eq.) in DMF (1.0 mL) was addedtetrakis(triphenylphosphane) palladium (35.58 mg; 0.03 mmol; 0.10 eq.).The mixture was degassed and heated at 105° C. for 15 h. The solutionwas cooled to room temperature and diluted with water and AcCN, andpurified by preparative HPLC to give2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(3-methyloxolan-3-yl)acetamide(26.6 mg). ¹H NMR (400 MHz, Methanol-d₄) δ 8.74 (s, 1H), 8.37 (s, 1H),4.60 (d, J=16.7 Hz, 1H), 4.52 (d, J=16.7 Hz, 1H), 4.02 (d, J=9.0 Hz,1H), 4.00 (s, 3H), 3.96-3.82 (m, 2H), 3.56 (d, J=9.0 Hz, 1H), 3.51 (s,3H), 3.30 (d, J=12.2 Hz, 2H), 3.10 (t, J=7.9 Hz, 2H), 2.33 (ddd, J=12.9,7.6, 5.3 Hz, 1H), 2.23 (p, J=7.8 Hz, 2H), 1.95 (dt, J=12.9, 8.1 Hz, 1H),1.46 (s, 3H). LCMS (ES) [M+1]⁺ m/z: 371.0.

Example 1.151 Synthesis of2-[methyl({2-[4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]-N-(1-methyl-1H-pyrazol-4-yl)acetamide(Compound 177)

Scheme 98 depicts a synthetic route for preparing an exemplary compound.

Step 1

To a solution of [(tert-butoxycarbonyl)(methyl)amino]acetic acid (2.00g; 10.57 mmol; 1.00 eq.) in DMF (15 mL) was added1-methyl-1H-pyrazol-4-ylamine (1.54 g; 15.86 mmol; 1.50 eq.), followedby Hunig's base (2.77 mL; 15.86 mmol; 1.50 eq.) and HATU (4.82 g; 12.68mmol; 1.20 eq.). After being stirred for 4 h, the mixture was dilutedwith Sat. NaHCO₃, and the aqueous layer was extracted with EtOAc. Theorganic layers were combined, washed with brine, dried, and concentratedto give the crude product, which was purified by silica gel columnchromatography (Hexanes/EtOAc=1:3) to give tert-butylN-methyl-N-{[(1-methyl-1H-pyrazol-4-yl)carbamoyl]methyl}carbamate (2.75g, 97% yield). LCMS (ES⁺): (M+Na)⁺=291.1.

Step 2

To a solution of tert-butylN-methyl-N-{[(1-methyl-1H-pyrazol-4-yl)carbamoyl]methyl}carbamate (2.75g; 10.25 mmol; 1.00 eq.) in DCM (5 mL) was added 4N HCl in dioxane (5mL). The mixture was stirred for 2 h. HPLC was used to check that thereaction was finished. The suspension was concentrated to give2-[chloro(methyl)amino]-N-(1-methyl-1H-pyrazol-4-yl)acetamide (2.15 g).LCMS (ES⁺): (M+H)⁺=169.1.

Step 3

To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine(1.32 g; 7.00 mmol; 1.00 eq.) in AcCN (15 ml) was added triethylamine(2.94 mL; 21.01 mmol; 3.00 eq.) and2-[chloro(methyl)amino]-N-(1-methyl-1H-pyrazol-4-yl)acetamide (2.15 g;10.51 mmol; 1.50 eq.). The mixture was heated at 80° C. for 3 h anddiluted with water. AcCN was removed under vacuum and the aqueous layerwas extracted with EtOAc. The organic layers were combined, washed withbrine, dried and concentrated. The resulting crude solid was washed withEtOAc, filtered, and dried to give2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(1-methyl-1H-pyrazol-4-yl)acetamideas a white solid (1.61 g). LCMS (ES⁺): (M+H)⁺=321.1.

Step 4

Synthesis of the Stille tin reagent: To a solution of2-bromo-4-(2,2,2-trifluoroethoxy)pyridine (310.00 mg; 1.21 mmol; 1.00eq.) in toluene (10 ml) at −78° C. was added butyllithium (0.54 mL; 2.70mol/L; 1.45 mmol; 1.20 eq.). After being stirred for 30 min at −78° C.,to the mixture was added tributyl(chloro)stannane (0.36 mL; 1.33 mmol;1.10 eq.). After being stirred for 30 min at −78° C., the solution waswarmed to room temperature and further stirred for 2 h. The mixture wasquenched with ice water and brine and extracted with hexane. The organiclayers were combined, dried, and concentrated to give2-(tributylstannyl)-4-(2,2,2-trifluoroethoxy)pyridine (590 mg).

To a solution of2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(1-methyl-1H-pyrazol-4-yl)acetamide(175.00 mg; 0.55 mmol; 1.00 eq.) in DMF (2 mL) was added the abovesynthesized 2-(tributylstannyl)-4-(2,2,2-trifluoroethoxy)pyridine(508.64 mg; 1.09 mmol; 2.00 eq.) and tetrakis(triphenylphosphane)palladium (63.04 mg; 0.05 mmol; 0.10 eq.). After being degassed with N₂,the mixture was heated at 110 degree for 15 h. The mixture was cooledand diluted with AcCN/water, filtered, and the filtrate was subjected topurification by preparative HPLC to give2-[methyl({2-[4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]-N-(1-methyl-1H-pyrazol-4-yl)acetamide(11.4 mg). LCMS (ES⁺): (M+H)⁺=462.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.74(s, 1H), 8.68 (d, J=5.8 Hz, 1H), 7.94 (s, 1H), 7.50 (d, J=2.3 Hz, 1H),7.43 (dd, J=5.8, 2.6 Hz, 1H), 6.33 (d, J=2.2 Hz, 1H), 5.01 (dd, J=9.3,4.1 Hz, 2H), 4.61 (s, 2H), 3.69 (s, 3H), 3.51 (s, 3H), 3.31 (m, 2H),3.01 (t, J=7.9 Hz, 2H), 2.14-2.03 (m, 2H).

Example 1.152 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide(Compound 187)

Scheme 99 depicts a synthetic route for preparing an exemplary compound.

Step 1

Into a 1 L 3-necked round-bottom flask was placedN-(tert-butoxycarbonyl)-N-methylglycine (40.0 g, 0.211 mol, 1.00 equiv),DMF (300 mL), 6-methoxypyridin-3-amine (28.8 g, 0.232 mol, 1.10 equiv),DIEA (54.4 g, 0.422 mmol, 2.00 equiv). This was followed by the additionof HATU (88.16 g, 0.232 mol, 1.10 equiv) in several batches at 0° C.After addition, the resulting solution was stirred for 16 h at roomtemperature. The reaction was quenched with 400 mL of water, extractedwith 3×200 mL of ethyl acetate. The combined organic phase was washedwith 2×400 mL of water and 1×400 mL brine, dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated under reducedpressure, the residue was purified by silica gel column with ethylacetate/petroleum ether (1:1). This resulted in 40 g (4%) of tert-butyl(2-((6-methoxypyridin-3-yl)amino)-2-oxoethyl)(methyl)carbamate as an offwhite solid. LCMS (ES) [M+1]⁺ m/z: 296.

Step 2

Into a 500-mL 3-round-bottom flask was placed tert-butyl(2-((6-methoxypyridin-3-yl)amino)-2-oxoethyl)(methyl)carbamate (40 g,0.101 mol, 1.00 equiv), DCM (200.00 mL). This was followed by theaddition of HCl (g) (2 M in ethyl acetate) (300.00 mL) dropwise withstirring at 0° C. The resulting solution was stirred for 16 h at roomtemperature, concentrated in vacuum to remove the solvent and washedwith ethyl acetate (150 mL). This resulted in 25.5 g (81%) ofN-(6-methoxypyridin-3-yl)-2-(methylamino)acetamide hydrochloride. LCMS(ES) [M−HCl+1]⁺ m/z: 196.

Step 3

Into a 1 L 3 neck round-bottom flask was placedN-(6-methoxypyridin-3-yl)-2-(methylamino)acetamide hydrochloride (38.6g, 0.167 mol, 1.05 equiv), NMP (300.00 mL),2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (30 g, 0.158 mol,1.00 equiv), DIEA (61.15 g, 0.474 mol, 3.00 equiv). The resultingsolution was stirred for 18 h at 50° C. in oil bath. The reactionmixture was cooled to room temperature, diluted with 200 mL of water,extracted with 3×200 mL of ethyl acetate. The combined organic phase waswashed with 3×300 ml of water and brine 200 mL, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated under reducedpressure, the residue was purified by silica gel column withTHF/petroleum ether (1:1). This resulted in 35 g (63%) of2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamideas a white solid. LCMS (ES) [M+1]⁺ m/z: 348.

Step 4

Into a 500-mL three necked round bottom flask purged and maintained withan inert atmosphere of nitrogen was placed2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide(10 g, 28.8 mmol, 1.00 equiv), toluene (150 mL),4-fluoro-2-(tributylstannyl)pyridine (20 g, 51.84 mmol, 1.8 equiv) andPd(PPh₃)₄ (3.04 g, 2.88 mmol, 0.10 equiv). The mixture was stirred for36 h at 110° C. in oil bath. The reaction was repeated in 2 batches. Thereaction mixture was cooled to room temperature, concentrated to removethe solvent, the residue was purified by silica gel column with PE/THF(100:1 to 1:10). This resulted in 12.1 g (51.5%) of2-((2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamideas yellow oil. LCMS (ES) [M+1]⁺ m/z: 409.

Step 5

Into a 250 mL 3-neck flask was placed ethane-1,2-diol (4.78 g, 77.0mmol, 5.0 equiv) and DMSO (100 mL), NaH (60% in mineral oil) (3.08 g,77.0 mmol, 5.0 equiv) was added in portion wise at 5° C. The mixture wasstirred for 1 h at room temperature. After which2-((2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide(6.3 g, 15.4 mmol, 1.00 equiv) was added at 5° C. The reaction mixturewas stirred for 5 h at room temperature. (The reaction was repeated in 2batches). The reaction mixture was poured into 200 mL of stirred water,extracted with 3×200 mL of ethyl acetate. The combined organic phase waswashed with 3×300 ml of water and brine 1×200 mL, dried over anhydroussodium sulfate. The residue was purified by Prep-HPLC with conditions:column, C18-800 g, Mobile phase, CH₃CN/H₂O (0.05% FA), from 10%increased to 70% within 27 min, Flow rate, 180 mL/min, Detector, 254 nm.The pH value of the fraction was adjusted to 7˜8 with K₂CO₃ solid,extracted with dichloromethane (3×300 mL). The combined organic phasewas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure. The residue was freeze dried togive 5.7 g (41%) of2-((2-(4-(2-hydroxyethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamideas a white solid. LCMS: (ES, m/z): [M+H]⁺: 451.2. ¹H-NMR: (300 MHz,DMSO-d₆, ppm): δ 10.27 (s, 1H), 8.44 (d, J=5.6 Hz, 1H), 8.35 (d, J=2.6Hz, 1H), 7.89 (dd, J=8.9, 2.7 Hz, 1H), 7.79 (d, J=2.5 Hz, 1H), 7.01 (dd,J=5.7, 2.6 Hz, 1H), 6.78 (d, J=8.9 Hz, 1H), 4.91 (t, J=5.4 Hz, 1H), 4.41(s, 2H), 4.04 (t, J=4.8 Hz, 2H), 3.80 (s, 3H), 3.69 (q, J=5.1 Hz, 2H),3.37 (s, 3H), 3.20 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.08-1.96(m, 2H).

Example 1.153 Synthesis ofN-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 348)

Scheme 100 depicts a synthetic route for preparing an exemplarycompound.

Step 1: Addition of Fluoropyridine

Into a 250-mL three-necked round bottom flask purged and maintained withan inert atmosphere of nitrogen were placedN-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(10 g, 33.8 mmol, 1.00 equiv), toluene (150.00 mL),4-fluoro-2-(tributylstannyl)pyridine (21.7 g, 60.84 mmol, 1.8 equiv),and Pd(PPh₃)₄ (3.57 g, 3.38 mmol, 0.10 equiv). After being stirred for60 h at 110° C. in an oil bath, the reaction mixture was cooled to roomtemperature, and concentrated to remove the solvent; the residue waspurified by silica gel column with dichloromethane/methanol (10:1). Thisresulted in 7 g (58%) ofN-(tert-butyl)-2-((2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide as a yellow solid. LCMS (ES) [M+1]⁺ m/z: 358.

Step 2: Addition of 2-(dimethylamino)ethan-1-ol

Into a 50 mL 3-neck flask were placed 2-(dimethylamino)ethan-1-ol (112mg, 1.26 mmol, 3.0 equiv) and DMF (2 mL). NaH (60% in mineral oil) (33.6mg, 0.84 mmol, 2.0 equiv) was added portion-wise at 0-5° C. After beingstirred for 1 h, to the mixture was addedN-(tert-butyl)-2-((2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(150 mg, 0.42 mmol, 1.00 equiv) at 0-5° C. The reaction mixture was thenstirred for 5 h at 50° C. After being cooled down to ambienttemperature, the reaction mixture was concentrated, and the residue waspurified by Prep-HPLC with the following conditions: column, C18-800 g,Mobile phase, CH₃CN/H₂O (0.05% FA), from 10% increased to 70% within 27min, Flow rate, 80 mL/min, Detector, 254 nm. The pH value of thefraction was adjusted to 7˜8 with Na₂CO₃, and the mixture was extractedwith dichloromethane (3×300 mL). The combined organic phases were driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. This resulted in 100.9 mg (56%) ofN-(tert-butyl)-2-((2-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a white solid. LCMS (ES, m/z): [M+H]⁺: 427. ¹H NMR (300 MHz, DMSO-d₆)δ 8.47 (d, J=5.6 Hz, 1H), 7.83 (d, J=2.5 Hz, 1H), 7.67 (s, 1H), 7.05(dd, J=5.6, 2.6 Hz, 1H), 4.20 (t, J=5.7 Hz, 2H), 4.12 (s, 2H), 3.31 (s,3H), 3.15 (t, J=7.2 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.66 (t, J=5.7 Hz,2H), 2.23 (s, 6H), 2.05-1.94 (m, 2H), 1.25 (s, 9H).

Alternative Method: For Preparing Compound 348

Into a 500 mL round-bottom flask were added 4-chloropicolinonitrile (50g, 360 mmol, 1.00 equiv) in MeOH and NaOMe (1.95 g, 36.1 mmol, 0.1equiv). The mixture was stirred for 8 hours at room temperature under anitrogen atmosphere, and NH₄Cl (29.0 g, 541 mmol, 1.5 equiv) was added.The resulting mixture was further stirred for 16 hours at roomtemperature under a nitrogen atmosphere. The resulting mixture wasfiltered, the filtrate was concentrated under reduced pressure. Thisresulted in 4-chloropicolinimidamide hydrochloride (63.0 g, 90.90%) as abrown solid. LCMS (ES) [M−HCl+1]⁺ m/z 156.

Into a 1 L round-bottom flask were added 4-chloropicolinimidamidehydrochloride (60.0 g, 312 mmol, 1.00 equiv) in MeOH (600 mL), methyl2-oxocyclopentane-1-carboxylate (66.6 g, 468 mmol, 1.5 equiv), and NaOMe(42.18 g, 781 mmol, 2.5 equiv) in MeOH at room temperature. The mixturewas stirred for 40 hours at 70° C. under a nitrogen atmosphere. Theprecipitated solids were collected by filtration and washed with MeOH(1×1 500 mL). This resulted in2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (62g, 80.12%) as a brown solid. LCMS (ES) [M+1]⁺ m/z 248.

Into a 1 L 3-necked round-bottom flask were added2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (60g, 242 mmol, 1.00 equiv) in DCM and TEA (123 g, 1211 mmol, 5.0 equiv). Astirred mixture of Tf₂O (137 g, 484 mmol, 2.0 equiv) in DCM was addeddropwise at 0° C. The resulting mixture was stirred for an additional 2hours at 0° C. The reaction was quenched by the addition of NH₄Cl (aq.500 mL) at room temperature. The resulting mixture was extracted withDCM (3×600 mL), and the organic layers were combined and dried overanhydrous Na₂SO₄. The resulting mixture was filtered, and the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with PE/EA (3.1) to afford2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yltrifluoromethanesulfonate (63 g, 68.48) as an off-white solid. LCMS (ES)[M+1]⁺ m/z 380.

Into a 500 mL three-necked round bottom flask were added2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yltrifluoromethanesulfonate (24.0 g, 63.3 mmol, 1.00 equiv), TEA (25.6 g,253.2 mmol, 4.00 equiv), and dichloromethane (300 mL). This was followedby the addition of N-(tert-butyl)-2-(methylamino)acetamide hydrochloride(14.8 g, 82.3 mmol, 1.30 equiv) at room temperature. After being stirredfor 12 h, the reaction was quenched with H₂O (200 mL), extracted withdichloromethane (100 mL*1), and the organic layer was separated anddried over anhydrous sodium sulfate. The mixture was filtered, and thefiltrate was concentrated under reduced pressure. The residue wastriturated in ethyl acetate/hexane (1:3). The solid was collected byfiltration and dried under an infrared lamp for 3 h. This resulted in21.3 g (90%)N-(tert-butyl)-2-((2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas an off-white solid. LCMS (ES, m/z): [M+H]⁺: 374.

Into a 250 mL three-necked round bottom flask were added2-(dimethylamino)ethan-1-ol (2.86 g, 32.17 mmol, 2.00 equiv) and DMF (80mL). This was followed by the addition of t-BuOK (3.6 g, 32.17 mmol,2.00 equiv) at room temperature. The mixture was stirred for 0.5 h,N-(tert-butyl)-2-((2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(6.0 g, 16.08 mmol, 1.00 equiv) was added to the above mixture andstirred for additional 5 h at 60° C. The reaction mixture was cooled toroom temperature, quenched with H₂O (100 mL), and extracted with ethylacetate (100 mL*2). The combined organic phases were washed with brine(100 mL*2) and dried over anhydrous sodium sulfate. The mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by Prep-HPLC with the following conditions: C18-500g, CH₃CN/H₂O (NH₄HCO₃ 0.1%), from 15% to 70% in 30 min, Flow rate, 150mL/min, Detector, UV 254 nm. This resulted in 5.5 g (80.29%)N-(tert-butyl)-2-((2-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a brown solid. The solid was triturated in CH₃CN (120 mL), collectedby filtration and dried to giveN-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(5.5 g, 98.8%). LCMS (ES, m/z): [M+H]⁺: 427. ¹H NMR (300 MHz, DMSO-d6) δ8.47 (d, J=5.6 Hz, 1H), 7.84 (d, J=2.5 Hz, 1H), 7.68 (s, 1H), 7.05 (dd,J=5.7, 2.6 Hz, 1H), 4.20 (t, J=5.7 Hz, 2H), 4.12 (s, 2H), 3.26 (s, 3H),3.14 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.67 (t, J=5.6 Hz, 2H),2.23 (s, 6H), 2.01-1.96 (m, 2H), 1.24 (s, 9H).

Example 1.154 Synthesis ofN-(2,3-dihydro-1H-inden-1-yl)-N-methyl-2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine

The title compound was synthesized in a similar manner to that ofcompound 92 by replacing azapane with N-methyl-1-indanamine. MS (ES+):(M+H)⁺=342.9. ¹H NMR (400 MHz, Chloroform-d) δ 8.78 (d, J=5.6 Hz, 1H),8.38 (d, J=7.9 Hz, 1H), 7.83-7.74 (m, 1H), 7.36 (dd, J=7.6, 4.8 Hz, 1H),7.32-7.27 (m, 1H), 7.25-7.14 (m, 2H), 6.44 (t, J=8.2 Hz, 1H), 3.21 (t,J=7.3 Hz, 2H), 3.14-3.03 (m, 3H), 3.03-2.91 (m, 4H), 2.56-2.43 (m, 1H),2.18-2.05 (m, 3H).

Example 1.155 Synthesis of2-{4-[(5aS,8aS)-octahydro-2H-cyclopenta[b][1,4]oxazepin-5-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl}pyridine(Compound 18)

Step 1

To a solution of tert-butyl N-[(1S,2S)-2-hydroxycyclopentyl]carbamate(1.24 g; 6.16 mmol; 1.00 eq.) in tert-butanol (20 mL) and tert-butylprop-2-enoate (20 mL) was added cesium carbonate (2.0 g; 6.16 mmol; 1.00eq.), the mixture was stirred at room temperature for 15 h, heated up to50° C. and stirred for 8 h. The solution was diluted with EtOAc, washedwith brine, and extracted with EtOAc. Organic layers were combined,dried and concentrated, the residue was purified by columnchromatography to give tert-butyl3-{[(1S,2S)-2-{[(tert-butoxy)carbonyl]amino}cyclopentyl]oxy}propanoate(1.22 g, 60.1%).

Step 2

A solution of tert-butyl3-{[(1S,2S)-2-{[(tert-butoxy)carbonyl]amino}cyclopentyl]oxy}propanoate(1.22 g; 3.70 mmol; 1.00 eq.) in 4N HCl in dioxane (20 mL) was stirredfor 15 h at room temperature, the mixture was concentrated to give3-{[(1S,2S)-2-(chloroamino)cyclopentyl]oxy}propanoic acid as thick oil(0.98 g, 126%), which was used for next step without purification. LCMS(ES) (M+H)⁺=174.4.

Step 3

To a solution of 3-{[(1S,2S)-2-aminocyclopentyl]oxy}propanoic acid (1.00g; 5.77 mmol; 1.00 eq.) in DCM (125 mL) was added Hunig's base (5.03 mL;28.87 mmol; 5.00 eq.) and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (5.16mL; 8.66 mmol; 1.50 eq.), after stirred at room temperature for 15 h,HPLC check desired mass found. The mixture was concentrated and theresidue was purified by column chromatography (DCM/MeOH=10:1) to give(5aS,8aS)-octahydro-2H-cyclopenta[b][1,4]oxazepin-4-one (460 mg, 51%).LCMS (ES) (M+H)⁺=156.2.

Step 4

To a solution of (5aS,8aS)-octahydro-2H-cyclopenta[b][1,4]oxazepin-4-one(200.00 mg; 1.29 mmol; 1.00 eq.) in THE (4.5 mL) was added lithiumaluminum hydride (1.29 mL; 2.00 mol/L; 2.58 mmol; 2.00 eq.) at roomtemperature. The mixture was then heated at 55° C. for 2 h, additional 1eq of LiAH₄ was added. After 30 min, 1 more eq of LiAH₄ was added, afterstirred for another 30 min, the mixture was cooled in ice batch, added0.4 mL of water and 0.1 mL of 4M NaOH, the suspension was diluted withEtOAc (30 mL) and filtered through celite, the filtrate was concentratedto give (5aS,8aS)-octahydro-2H-cyclopenta[b][1,4]oxazepane (175 mg,96%), which was used for next step without further purification. LCMS(ES) (M+H)⁺=142.2.

Step 5

To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine(100.00 mg; 0.53 mmol; 1.00 eq.) and(5aS,8aS)-octahydro-2H-cyclopenta[b][1,4]oxazepine (93.37 mg; 0.66 mmol;1.25 eq.) in AcCN (1 mL) was added DIPEA (0.18 mL; 1.06 mmol; 2.00 eq.)at room temperature. The reaction mixture was stirred for 30 min atambient temperature, and 80° C. degree for overnight. The solution wasconcentrated and the crude oil was purified by column chromatography(Hexanes/EtOAc=2:1) to give4-[(5aS,8aS)-octahydro-2H-cyclopenta[b][1,4]oxazepin-5-yl]-2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine(130 mg, 83.6% yield). LCMS (ES) (M+H)⁺=293.5.

Step 6

To a solution of4-[(5aS,8aS)-octahydro-2H-cyclopenta[b][1,4]oxazepin-5-yl]-2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine(136.00 mg; 0.46 mmol; 1.00 eq.) in Toluene (2 mL) was added2-(tributylstannyl)pyridine (255.63 mg; 0.69 mmol; 1.50 eq.) followed bytetrakis(triphenylphosphane) palladium (53.49 mg; 0.05 mmol; 0.10 eq.).The solution was heated at 105° C. for 15 h, cooled and concentrated togive crude product, which was purified by preparative HPLC to give2-{4-[(5aS,8aS)-octahydro-2H-cyclopenta[b][1,4]oxazepin-5-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl}pyridine(101 mg, 64.5%). LCMS (ES) (M+H)⁺=337.3. ¹H NMR (400 MHz, DMSO-d6) δ8.74 (d, J=4.7 Hz, 1H), 8.31 (d, J=7.9 Hz, 1H), 8.01 (td, J=7.7, 1.8 Hz,1H), 7.57 (dd, J=7.5, 4.8 Hz, 1H), 4.40 (dd, J=15.3, 5.9 Hz, 1H), 4.23(tt, J=17.0, 10.0 Hz, 2H), 3.91-3.83 (m, 1H), 3.73 (dd, J=15.4, 10.9 Hz,1H), 3.52 (td, J=12.1, 2.5 Hz, 1H), 3.12 (dp, J=29.5, 7.3, 6.9 Hz, 2H),2.91 (t, J=7.9 Hz, 2H), 2.44-2.32 (m, 1H), 2.03 (dd, J=10.8, 5.0 Hz,2H), 2.01-1.83 (m, 2H), 1.78 (q, J=9.5, 8.4 Hz, 1H), 1.71 (t, J=4.3 Hz,1H), 1.70-1.63 (m, 1H), 1.56 (p, J=10.2 Hz, 1H), 1.44-1.30 (m, 1H).

Example 1.156 Synthesis of2-{4-[(5aS,8aS)-octahydro-2H-cyclopenta[b][1,4]oxazepin-5-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl}-4-methylpyridine(Compound 45)

Compound 45 was synthesized similar to Compound 18 by replacing2-(tributylstannyl)pyridine with 2-(tributylstannyl)pyridine. LCMS (ES)[M+1]⁺ m/z 351. ¹H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J=4.9 Hz, 1H), 8.10(d, J=15.7 Hz, 1H), 7.28 (d, J=4.9 Hz, 1H), 4.38 (dd, J=15.1, 5.9 Hz,1H), 4.18 (dtd, J=23.0, 10.0, 7.0 Hz, 2H), 3.91-3.82 (m, 1H), 3.64 (dd,J=15.3, 10.8 Hz, 1H), 3.49 (td, J=12.0, 2.5 Hz, 1H), 3.16-3.00 (m, 2H),2.83 (dd, J=8.7, 7.1 Hz, 2H), 2.41 (s, 1H), 2.39 (s, 3H), 2.00 (p, J=7.6Hz, 2H), 1.94-1.84 (m, 2H), 1.79-1.63 (m, 3H), 1.55 (p, J=10.3 Hz, 1H),1.40-1.25 (m, 1H).

Example 1.157 Synthesis of1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepan-2-one(Compound 46)

Step 1

To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine(100.00 mg; 0.53 mmol; 1.00 eq.) and 2-azepanone (65.84 mg; 0.58 mmol;1.10 eq.) in Dioxane (2 mL) was added Cesium carbonate (258.53 mg; 0.79mmol; 1.50 eq.), Xantphos (30.61 mg; 0.05 mmol; 0.10 eq.) andTris(dibenzylideneacetone)dipalladium(0) (24.22 mg; 0.03 mmol; 0.05eq.). After heated at 100° C. for 3 h, the mixture was diluted withAcCN, filtered through celite, the filtrate was concentrated andpurified by preparative HPLC to give1-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}azepan-2-one (16 mg,11% yield). LCMS (ES) (M+H)⁺=342.7.

Step 2

To a solution of 2-(tributylstannyl)pyridine (44.33 mg; 0.12 mmol; 2.00eq.) and 1-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}azepan-2-one(16.00 mg; 0.06 mmol; 1.00 eq.) in toluene (1 mL) was addedtetrakis(triphenylphosphane) palladium (6.96 mg; 0.01 mmol; 0.10 eq.),after degassed and heated at 100° C. overnight, it was concentrated andthe residue was subjected to purification by preparative HPLC to give1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepan-2-one(5.4 mg, 29.1%). LCMS (ES) (M+H)⁺=308.9. ¹H NMR (400 MHz, DMSO-d₆) δ8.77-8.71 (m, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.99 (dd, J=8.5, 6.8 Hz, 1H),7.54-7.47 (m, 1H), 3.92 (d, J=8.4 Hz, 2H), 2.95 (t, J=7.8 Hz, 2H), 2.64(d, J=10.5 Hz, 2H), 2.15-2.03 (m, 2H), 1.80-1.68 (m, 8H).

Example 1.158 Synthesis of2-{4-[(5aS,8aR)-octahydro-2H-cyclopenta[b][1,4]oxazepin-5-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl}pyridine(Compound 48)

Compound 48 was synthesized similar to Compound 18 by replacingtert-butyl N-[(1S,2S)-2-hydroxycyclopentyl]carbamate with tert-butylN-[(1S,2R)-2-hydroxycyclopentyl]carbamate. LCMS (ES) [M+1]⁺ m/z: 337.1.¹H NMR (400 MHz, Methanol-d₄) δ 8.69 (dt, J=4.8, 1.3 Hz, 1H), 8.33 (dd,J=8.0, 1.1 Hz, 1H), 7.95 (td, J=7.8, 1.8 Hz, 1H), 7.50 (ddd, J=7.6, 4.8,1.2 Hz, 1H), 5.04-4.93 (m, 1H), 4.16 (dt, J=14.1, 4.1 Hz, 1H), 4.00 (s,1H), 4.02-3.92 (m, 1H), 3.68 (ddd, J=15.2, 10.6, 5.2 Hz, 1H), 3.43 (ddd,J=12.5, 9.9, 6.2 Hz, 1H), 3.22-3.11 (m, 2H), 3.14-3.04 (m, 1H), 2.97 (t,J=7.9 Hz, 2H), 2.23-1.84 (m, 7H), 1.81-1.58 (m, 2H).

Example 1.159 Synthesis of2-{4-[(5aS,8aR)-octahydro-2H-cyclopenta[b][1,4]oxazepin-5-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl}-4-methylpyridine(Compound 49)

Compound 49 was synthesized similar to Compound 18 by replacingtert-butyl N-[(1S,2S)-2-hydroxycyclopentyl]carbamate with tert-butylN-[(1S,2R)-2-hydroxycyclopentyl]carbamate and replacing2-(tributylstannyl)pyridine with 2-(tributylstannyl)pyridine. LCMS (ES)[M+1]⁺ m/z: 351.3. ¹H NMR (400 MHz, Methanol-d₄) δ 8.54 (d, J=5.0 Hz,1H), 8.15 (s, 1H), 7.37 (dd, J=5.2, 1.6 Hz, 1H), 5.00 (dq, J=10.5, 4.5Hz, 1H), 4.19 (dt, J=14.6, 4.2 Hz, 1H), 3.99 (ddd, J=15.8, 6.6, 3.4 Hz,2H), 3.69 (ddd, J=15.2, 10.5, 5.3 Hz, 1H), 3.44 (ddd, J=12.5, 9.9, 6.3Hz, 1H), 3.23-3.12 (m, 1H), 3.16-3.05 (m, 2H), 2.98 (t, J=7.9 Hz, 2H),2.47 (s, 3H), 2.24-1.85 (m, 7H), 1.82-1.58 (m, 2H).

Example 1.160 Synthesis of2-{4-[(5aS,8aR)-octahydro-2H-cyclopenta[b][1,4]oxazepin-5-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl}-4-methoxypyridine(Compound 54)

Compound 54 was synthesized similar to Compound 18 by replacingtert-butyl N-[(1S,2S)-2-hydroxycyclopentyl]carbamate with tert-butylN-[(1S,2R)-2-hydroxycyclopentyl]carbamate and replacing2-(tributylstannyl)pyridine with 4-methoxy-2-(tributylstannyl)pyridine.LCMS (ES) [M+1]⁺ m/z: 367.2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.50 (d,J=5.8 Hz, 1H), 7.87 (d, J=2.6 Hz, 1H), 7.10 (dd, J=5.9, 2.6 Hz, 1H),4.98 (td, J=9.7, 8.9, 4.3 Hz, 1H), 4.14 (dt, J=14.6, 4.2 Hz, 1H),4.05-3.93 (m, 2H), 3.96 (s, 3H), 3.68 (ddd, J=15.2, 10.5, 5.2 Hz, 1H),3.44 (ddd, J=12.5, 10.0, 6.2 Hz, 1H), 3.22-3.12 (m, 1H), 3.14-3.04 (m,1H), 2.95 (t, J=7.9 Hz, 2H), 2.23-1.84 (m, 5H), 2.03 (s, 3H), 1.81-1.69(m, 1H), 1.69-1.59 (m, 1H).

Example 1.161 Synthesis ofN-(1-hydroxy-2-methylpropan-2-yl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 148)

Compound 148 was synthesized similar to Compound 144 by replacingcyclohexylamine with 2-amino-2-methyl-1-propanol. LCMS (ES) [M+1]⁺ m/z416. ¹H NMR (300 MHz, DMSO-d₆) δ 8.47 (d, J=5.6 Hz, 1H), 7.84 (d, J=2.6Hz, 1H), 7.50 (s, 1H), 7.04 (dd, J=5.6, 2.6 Hz, 1H), 4.90 (br, 1H),4.28-4.07 (m, 4H), 3.76 (t, J=5.0 Hz, 2H), 3.37 (s, 2H), 3.25 (s, 3H),3.14 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.05-1.94 (m, 2H), 1.18(s, 6H).

Example 1.162 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(oxolan-3-yl)acetamide(Compound 149)

Compound 149 was synthesized similar to Compound 144 by replacingcyclohexylamine with oxolan-3-amine hydrochloride. LCMS (ES) [M+1]⁺ m/z414. ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 8.46 (d, J=5.6 Hz, 1H), 8.37 (d,J=6.9 Hz, 1H), 7.80 (d, J=2.6 Hz, 1H), 7.04 (dd, J=5.6, 2.6 Hz, 1H),5.22-4.75 (m, 1H), 4.34-4.12 (m, 5H), 3.83-3.52 (m, 5H), 3.49-3.39 (m,1H), 3.27 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H),2.15-1.89 (m, 3H), 1.79-1.68 (m, 1H).

Example 1.163 Synthesis ofN-cyclopentyl-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 150)

Compound 150 was synthesized similar to Compound 142 by replacingcyclohexylamine with cyclopentanamine. LCMS (ES, m/z): [M+H]⁺: 355.¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 8.05 (d, J=7.5 Hz, 1H), 7.71 (s, 1H),7.60 (s, 1H), 4.11 (s, 2H), 4.02 (q, J=6.6, 13.5 Hz, 1H), 3.69 (s, 3H),3.22 (s, 3H), 3.07 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.8 Hz, 2H), 1.99-1.89(m, 2H), 1.80-1.72 (m, 2H), 1.63-1.34 (m, 6H).

Example 1.164 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6-methoxypyridin-3-yl)acetamide(Compound 151)

Compound 151 was synthesized similar to Compound 135 by replacingoxolan-3-amine with 5-amino-2-methoxypyridine. LCMS (ES, m/z): [M+H]⁺:421. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 10.26 (s, 1H), 8.45 (d, J=5.4 Hz,1H), 8.34 (d, J=2.7 Hz, 1H), 7.87 (dd, J=9.0, 2.7 Hz, 1H), 7.79 (d,J=2.7 Hz, 1H), 7.01 (dd, J=5.4, 2.4 Hz, 1H), 6.78 (d, J=9.0 Hz, 1H),4.40 (s, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.37 (s, 3H), 3.21 (t, J=7.5Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.08-1.94 (m, 2H).

Example 1.165 Synthesis ofN-(5-methoxypyridin-2-yl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 152)

Compound 152 was synthesized similar to Compound 135 by replacingoxolan-3-amine with 5-methoxypyridin-2-amine. LCMS (ES, m/z): [M+H]⁺:421. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 10.55 (s, 1H), 8.43 (d, J=5.7 Hz,1H), 8.03 (d, J=3.0 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.76 (d, J=2.7 Hz,1H), 7.39 (dd, J=9.0, 3.0 Hz, 1H), 6.96 (dd, J=5.7, 2.7 Hz, 1H), 4.49(s, 2H), 3.79 (s, 3H), 3.73 (s, 3H), 3.35 (s, 3H), 3.20 (t, J=7.5 Hz,2H), 2.83 (t, J=7.8 Hz, 2H), 2.08-1.95 (m, 2H).

Example 1.166 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(2-methoxypyrimidin-5-yl)acetamide(Compound 153)

Compound 153 was synthesized similar to Compound 135 by replacingoxolan-3-amine with 5-methoxypyridin-2-amine. LCMS (ES, m/z): [M+H]⁺:421. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 10.55 (s, 1H), 8.43 (d, J=5.7 Hz,1H), 8.03 (d, J=3.0 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.76 (d, J=2.7 Hz,1H), 7.39 (dd, J=9.0, 3.0 Hz, 1H), 6.96 (dd, J=5.7, 2.7 Hz, 1H), 4.49(s, 2H), 3.79 (s, 3H), 3.73 (s, 3H), 3.35 (s, 3H), 3.20 (t, J=7.5 Hz,2H), 2.83 (t, J=7.8 Hz, 2H), 2.08-1.95 (m, 2H).

Example 1.167 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(1-methyl-1H-pyrazol-4-yl)acetamide(Compound 154)

Compound 154 was synthesized similar to Compound 135 by replacingoxolan-3-amine with 1-methylpyrazol-4-amine. LCMS (ES, m/z): [M+H]⁺:394. ¹H NMR (300 MHz, DMSO-d₆) δ 10.24 (s, 1H), 8.47 (d, J=5.4 Hz, 1H),7.83 (s, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.38 (s, 1H), 7.01 (dd, J=5.7, 2.4Hz, 1H), 4.35 (s, 2H), 3.82 (s, 3H), 3.76 (s, 3H), 3.34 (s, 3H), 3.19(t, J=7.5 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.08-1.95 (m, 2H).

Example 1.168 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(1-methylcyclopentyl)acetamide(Compound 155)

Compound 155 was synthesized similar to Compound 135 by replacing 2oxolan-3-amine with 1-methylcyclopentan-1-amine hydrochloride. LCMS (ES,m/z): [M+H]⁺: 396. ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (d, J=5.7 Hz, 1H),7.84 (d, J=2.4 Hz, 1H), 7.74 (s, 1H), 7.04 (dd, J=5.7, 2.7 Hz, 1H), 4.14(s, 2H), 3.89 (s, 3H), 3.26 (s, 3H), 3.14 (t, J=7.5 Hz, 2H), 2.82 (t,J=7.8 Hz, 2H), 2.06-1.87 (m, 4H), 1.63-1.38 (m, 6H), 1.27 (s, 3H).

Example 1.169 Synthesis ofN-tert-butyl-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-methylacetamide(Compound 156)

Compound 156 was synthesized similar to Compound 135 by replacingoxolan-3-amine with tert-butyl(methyl)amine. LCMS (ES, m/z): [M+H]⁺:384. ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (d, J=5.7 Hz, 1H), 7.79 (d, J=2.4Hz, 1H), 7.03 (dd, J=5.7, 2.7 Hz, 1H), 4.43 (s, 2H), 3.89 (s, 3H), 3.25(s, 3H), 3.11 (t, J=7.5 Hz, 2H), 2.93 (s, 3H), 2.80 (t, J=7.8 Hz, 2H),2.08-1.95 (m, 2H), 1.32 (s, 9H).

Example 1.170 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N,N-dimethylacetamide(Compound 157)

Compound 157 was synthesized similar to Compound 135 by replacingoxolan-3-amine with dimethylamine hydrochloride. LCMS (ES, m/z): [M+H]⁺:342. ¹H NMR (300 MHz, DMSO-d₆) δ 8.47 (d, J=5.7 Hz, 1H), 7.74 (d, J=2.4Hz, 1H), 7.02 (dd, J=5.7, 2.7 Hz, 1H), 4.51 (s, 2H), 3.89 (s, 3H), 3.25(s, 3H), 3.12 (t, J=7.5 Hz, 2H), 3.05 (s, 3H), 2.85 (s, 3H), 2.81 (t,J=7.8 Hz, 2H), 2.03-1.93 (m, 2H).

Example 1.171 Synthesis ofN-tert-butyl-2-{[2-(4-cyanopyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 158)

Compound 158 was synthesized similar to Compound 24 by replacing4-methyl-2-(tributylstannyl)-pyridine with2-(trimethylstannyl)pyridine-4-carbonitrile. LCMS (ES) [M+1]⁺ m/z 365.¹H NMR (300 MHz, DMSO-d₆) δ 8.92 (d, J=4.9 Hz, 1H), 8.66 (s, 1H), 7.92(dd, J=5.0, 1.6 Hz, 1H), 7.76 (s, 1H), 4.14 (s, 2H), 3.32 (s, 3H), 3.19(t, J=7.3 Hz, 2H), 2.84 (t, J=7.8 Hz, 2H), 2.01 (t, J=7.6 Hz, 2H).

Example 1.172 Synthesis ofN-tert-butyl-2-({2-[4-(cyclopropylmethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 159)

Compound 159 was synthesized similar to Compound 24 by replacing4-methyl-2-(tributylstannyl)-pyridine with4-(cyclopropylmethoxy)-2-(trimethylstannyl)pyridine. LCMS (ES) [M+1]⁺m/z 410. ¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (d, J=5.6 Hz, 1H), 7.85 (d,J=2.5 Hz, 1H), 7.69 (s, 1H), 7.01 (dd, J=5.7, 2.6 Hz, 1H), 4.12 (s, 2H),3.97 (d, J=7.1 Hz, 2H), 3.27 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.81 (t,J=7.9 Hz, 2H), 2.04-1.88 (m, 2H), 1.25 (s, 9H), 1.25-1.20 (m, 1H),0.66-0.54 (m, 2H), 0.43-0.32 (m, 2H).

Example 1.173 Synthesis ofN-tert-butyl-2-{methyl[2-(1-methyl-1H-pyrazol-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 160)

Compound 160 was synthesized similar to Compound 24 by replacing4-methyl-2-(tributylstannyl)-pyridine with1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole. LCMS(ES) [M+1]⁺ m/z: 343. ¹H NMR (300 MHz, DMSO-d6) δ 7.69 (d, J=2.2 Hz,1H), 7.60 (s, 1H), 6.81 (d, J=2.2 Hz, 1H), 4.09 (s, 2H), 3.89 (s, 3H),3.21 (s, 3H), 3.08 (t, J=7.3 Hz, 2H), 2.75 (t, J=7.8 Hz, 2H), 2.13-1.84(m, 2H), 1.24 (s, 9H).

Example 1.174 Synthesis of2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(1-methylcyclopentyl)acetamide(Compound 161)

Compound 161 was synthesized similar to Compound 142 by replacingcyclohexylamine with 1-methylcyclopentan-1-amine. LCMS (ES, m/z):[M+H]⁺: 369. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 8.16 (s, 1H), 7.74 (d,J=1.5 Hz, 1H), 7.71 (br, 1H), 7.61 (d, J=1.5 Hz, 1H), 4.10 (s, 2H), 3.69(s, 3H), 3.22 (s, 3H), 3.07 (t, J=7.5 Hz, 2H), 2.74 (t, J=7.8 Hz, 2H),1.99-1.89 (m, 4H), 1.60-1.44 (m, 6H), 1.29 (s, 3H).

Example 1.175 Synthesis ofN-tert-butyl-2-{methyl[2-(1-methyl-1H-imidazol-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 162)

Compound 162 was synthesized similar to Compound 24 by replacing4-methyl-2-(tributylstannyl)-pyridine with1-methyl-2-(tributylstannyl)-1H-imidazole. LCMS (ES) [M+1]⁺ m/z: 343. ¹HNMR (300 MHz, DMSO-d6) δ 7.68 (d, J=1.2 Hz, 1H), 7.62-7.54 (m, 2H), 4.11(s, 2H), 3.97 (s, 3H), 3.21 (s, 3H), 3.09 (t, J=7.2 Hz, 2H), 2.75 (t,J=7.8 Hz, 2H), 1.95 (m, 2H), 1.25 (s, 9H).

Example 1.176 Synthesis ofN-tert-butyl-2-{methyl[2-(1,3-oxazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 163)

Compound 163 was synthesized similar to Compound 24 by replacing4-methyl-2-(tributylstannyl)-pyridine with2-(triisopropylsilyl)-4-(trimethylstannyl)oxazole. LCMS (ES) [M+1]⁺ m/z:330. ¹H NMR (300 MHz, DMSO-d6) δ 8.62 (d, J=1.1 Hz, 1H), 8.42 (d, J=1.1Hz, 1H), 7.60 (s, 1H), 4.10 (s, 2H), 3.23 (s, 3H), 3.10 (t, J=7.3 Hz,2H), 2.77 (t, J=7.9 Hz, 2H), 2.05-1.92 (m, 2H), 1.24 (s, 9H).

Example 1.177 Synthesis ofN-tert-butyl-2-{methyl[2-(1,3-oxazol-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 164)

Compound 164 was synthesized similar to Compound 24 by replacing4-methyl-2-(tributylstannyl)-pyridine with2-(trimethylstannyl)-1,3-oxazole. LCMS (ES) [M+1]⁺ m/z: 330. ¹H NMR (300MHz, DMSO-d6) δ 8.23 (d, J=0.7 Hz, 1H), 7.60 (s, 1H), 7.40 (d, J=0.8 Hz,1H), 4.16 (s, 2H), 3.20 (s, 3H), 3.11 (t, J=7.3 Hz, 2H), 2.80 (t, J=7.9Hz, 2H), 1.98-1.85 (m, 2H), 1.25 (s, 9H).

Example 1.178 Synthesis ofN-tert-butyl-2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 165)

Compound 165 was synthesized similar to Compound 24 by replacing4-methyl-2-(tributylstannyl)-pyridine with3-(trimethylstannyl)isoquinoline. LCMS (ES) [M+1]⁺ m/z: 390. ¹H NMR (300MHz, DMSO-d₆) δ 9.40 (s, 1H), 8.86 (s, 1H), 8.21-8.16 (m, 2H), 8.12 (d,J=8.2 Hz, 1H), 7.87-7.69 (m, 3H), 4.20 (s, 2H), 3.32 (s, 3H), 3.18 (t,J=7.3 Hz, 2H), 2.86 (t, J=7.8 Hz, 2H), 2.10-1.93 (m, 2H), 1.23 (s, 9H).

Example 1.179 Synthesis ofN-tert-butyl-2-[(2-{imidazo[1,2-a]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 166)

Compound 166 was synthesized similar to Compound 24 by replacing4-methyl-2-(tributylstannyl)-pyridine with2-(trimethylstannyl)imidazo[1,2-a]pyridine. LCMS (ES) [M+1]⁺ m/z 379. ¹HNMR (300 MHz, DMSO-d6) δ 8.52 (d, J=7.1 Hz, 2H), 7.68 (s, 1H), 7.57 (d,J=9.1 Hz, 1H), 7.31-7.19 (m, 1H), 6.92 (td, J=6.7, 1.2 Hz, 1H), 4.16 (s,2H), 3.25 (s, 3H), 3.11 (t, J=7.3 Hz, 2H), 2.79 (t, J=7.9 Hz, 2H),1.99-1.85 (m, 2H), 1.25 (s, 9H).

Example 1.180 Synthesis ofN-(3-fluorophenyl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 167)

Compound 167 was synthesized similar to Compound 144 by replacing1-cyclohexylamine with 3-fluoroaniline. LCMS (ES) [M+1]⁺ m/z 438. ¹H NMR(300 MHz, DMSO-d6) δ 10.46 (br, 1H), 8.43 (d, J=5.6 Hz, 1H), 7.78 (s,1H), 7.57 (d, J=11.2 Hz, 1H), 7.41-7.25 (m, 2H), 7.04-6.96 (m, 1H), 6.85(dd, J=8.4, 4.9 Hz, 1H), 5.18-4.62 (br, 1H), 4.55-4.31 (m, 2H),4.15-3.95 (m, 2H), 3.71-3.62 (m, 2H), 3.35 (s, 3H), 3.21 (t, J=7.2 Hz,2H) 2.83 (t, J=7.9 Hz, 2H), 2.22-1.98 (m, 2H).

Example 1.181 Synthesis ofN-[(1R,2S)-2-hydroxycyclohexyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 168)

Compound 168 was synthesized similar to Compound 135 by replacingoxolan-3-amine with (1R,2S)-2-aminocyclohexan-1-ol. LCMS (ES) [M+1]⁺m/z: 412. ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (d, J=5.6 Hz, 1H), 7.80 (d,J=2.6 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.03 (dd, J=5.6, 2.6 Hz, 1H),4.59 (d, J=3.9 Hz, 1H), 4.31 (d, J=16.6 Hz, 1H), 4.18 (d, J=16.6 Hz,1H), 3.89 (s, 3H), 3.71-3.58 (m, 2H), 3.25 (s 3H), 3.14 (t, J=7.1 Hz,2H), 2.82 (t, J=7.9 Hz, 2H), 2.03-1.91 (m, 2H), 1.67-1.15 (m, 8H).

Example 1.182 Synthesis ofN-[(1S,2R)-2-hydroxycyclohexyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 169)

Compound 169 was synthesized similar to Compound 135 by replacingoxolan-3-amine with (1S,2R)-2-aminocyclohexan-1-ol. LCMS (ES) [M+1]⁺m/z: 412. ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (d, J=5.6 Hz, 1H), 7.80 (d,J=2.6 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.03 (dd, J=5.6, 2.6 Hz, 1H),4.59 (d, J=3.9 Hz, 1H), 4.31 (d, J=16.7 Hz, 1H), 4.18 (d, J=16.7 Hz,1H), 3.89 (s, 3H), 3.71-3.63 (m, 2H), 3.25 (s, 3H), 3.14 (t, J=7.5 Hz,2H), 2.82 (t, J=7.9 Hz, 2H), 2.06-1.92 (m, 2H), 1.69-1.32 (m, 6H),1.31-1.14 (m, 2H).

Example 1.183a and Example 1.183b Synthesis ofN-[(1R,2S)-2-hydroxycyclopentyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 170) andN-[(1S,2R)-2-hydroxycyclopentyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 171)

Into a 50-mL round-bottom flask were placed[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]aceticacid (120 mg, 0.38 mmol, 1.00 equiv), DMF (5.00 mL), HATU (174 mg, 0.45mmol, 1.20 equiv), DIEA (148 mg, 1.145 mmol, 3.00 equiv), and(1S,2R)-2-aminocyclopentan-1-ol hydrochloride (63.04 mg, 0.45 mmol, 1.20equiv). The resulting solution was stirred for 3 hr at 25° C. The crudeproduct was purified by Prep-HPLC with the following conditions: Column,Xbridge Prep C18 OBD column, 5 um, 19*150 mm; mobile phase, Water (0.05%NH₃·H₂O) and CH₃CN (35% CH₃CN up to 50% in 10 min); Detector, UV 254 nm.The collected fractions were combined and concentrated under vacuum.

The resulting product was separated by Chiral HPLC with the followingconditions: Column: CHIRALPAK IC, 20*250 mm, 5 um; Mobile phase: A:n-Hexane/DCM=5:1, B: Ethanol+0.1% DEA; Flow rate: 90 mL/min; Gradient:30% B in 20 min. This resulted in 35.1 mg (23.13%) ofN-[(1R,2S)-2-hydroxycyclopentyl]-2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamideas a white solid and 37.2 mg (24.52%) ofN-[(1S,2R)-2-hydroxycyclopentyl]-2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamideas a white solid. The compounds were analyzed by analytical chiral HPLCwith the following conditions: Column: CHIRALPAK IC, 4.6*50 mm, 3 um;Mobile phase: A: n-Hexane/DCM=5:1, B: Ethanol+0.1% DEA; Flow rate: 1mL/min; Gradient: 30% B in 6 min.

Compound 170: CHIRAL_HPLC: Retention time 3.09 min. LCMS (ES, m/z):[M+H]⁺: 398. ¹H-NMR (300 MHz, DMSO-d6, ppm): δ 8.48 (d, J=5.6 Hz, 1H),7.81 (d, J=2.6 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.03 (dd, J=5.6, 2.6 Hz,1H), 4.65 (d, J=3.9 Hz, 1H), 4.32 (d, J=16.7 Hz, 1H), 4.19 (d, J=16.7Hz, 1H), 3.89 (s, 3H), 3.98-3.79 (m, 2H), 3.26 (s, 3H), 3.15 (t, J=7.5Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.05-1.94 (m, 2H), 1.74-1.68 (m, 3H),1.58-1.39 (m, 3H). Compound 171: CHIRAL_HPLC: Retention time 3.88 min.LCMS (ES, m/z): [M+H]⁺: 398. ¹H-NMR (300 MHz, DMSO-d6, ppm): δ ¹H-NMR:(300 MHz, DMSO-d6, ppm): δ 8.48 (d, J=5.6 Hz, 1H), 7.81 (d, J=2.6 Hz,1H), 7.65 (d, J=7.8 Hz, 1H), 7.03 (dd, J=5.6, 2.6 Hz, 1H), 4.65 (d,J=3.9 Hz, 1H), 4.32 (d, J=16.7 Hz, 1H), 4.19 (d, J=16.7 Hz, 1H), 3.89(s, 3H), 3.98-3.79 (m, 2H), 3.26 (s, 3H), 3.15 (t, J=7.5 Hz, 2H), 2.82(t, J=7.8 Hz, 2H), 2.05-1.94 (m, 2H), 1.74-1.68 (m, 3H), 1.58-1.39 (m,3H).

Example 1.183c and Example 1.183d Synthesis ofN-[(1R,2R)-2-hydroxycyclopentyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 172) andN-[(1S,2S)-2-hydroxycyclopentyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 173)

To a stirred solution of[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]aceticacid (300 mg, 0.95 mmol, 1.0 equiv), DIEA (616 mg, 4.77 mmol, 5.0equiv), and HATU (1.819 g, 4.77 mmol, 5.0 equiv) in THE (30 mL) wasadded (1R,2R)-2-aminocyclopentan-1-ol (482 mg, 4.77 mmol, 5.0 equiv) inportions at 20° C. The resulting mixture was stirred for 5 h at 60° C.The reaction was concentrated under reduced pressure. The residue waspurified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, C18; mobile phase A: CH₃CN, Mobile phase B:Water; Flow rate: 20 mL/min Column to give 200 mg of the racemateproduct, which was separated by Chiral-HPLC with the followingconditions: Column: Lux Amylose-1, 50*250 mm, 10 um; Mobile phase A:n-Hexane, Mobile phase B: Ethanol; Flow rate: 90 mL/min; Gradient: 50% Bin 36 min; 220 nm. This resulted inN-[(1R,2R)-2-hydroxycyclopentyl]-2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamide(85 mg, 22.41%) andN-[(1S,2S)-2-hydroxycyclopentyl]-2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamide(80 mg, 21.09%) as a white solid. The compounds were subjected toanalytical chiral HPLC with the following conditions: CHIRALPAK IC,4.6*50 mm, 3 um; Mobile phase: A: n-Hexane, Mobile phase B: Ethanol;Flow rate: 1 mL/min; Gradient: 50% B in 6 min.

Compound 172: CHIRAL_HPLC: Retention time 4.594 min. LCMS (ES, m/z):[M+H]⁺: 398.2; ¹H NMR (300 MHz, CDCl₃, ppm): δ 8.53 (d, J=5.7 Hz, 1H),8.21 (s, 1H), 7.95 (d, J=2.4 Hz, 1H), 6.88 (dd, J=5.4, 2.4 Hz, 1H), 4.46(br, 1H), 4.22 (s, 2H), 3.90 (s, 3H), 3.89-3.82 (m, 1H), 3.80-3.78 (m,1H), 3.40 (s, 3H), 3.19 (t, J=7.2 Hz, 2H), 2.99 (t, J=7.8 Hz, 2H),2.15-2.08 (m, 2H), 2.05-1.96 (m, 2H), 1.71-1.57 (m, 3H), 1.48-1.38 (m,1H).

Compound 173: CHIRAL_HPLC: Retention time 5.942 min. LCMS (ES, m/z):[M+H]⁺: 398.2; ¹H NMR (300 MHz, CDCl₃, ppm): δ 8.52 (d, J=8.7 Hz, 1H),8.20 (s, 1H), 7.95 (d, J=2.4 Hz, 1H), 6.88 (dd, J=2.7, 5.7 Hz, 1H), 4.48(br, 1H), 4.22 (br, 2H), 3.90 (s, 3H), 3.89-3.82 (m, 1H), 3.80-3.78 (m,1H), 3.40 (s, 3H), 3.18 (t, J=8.4 Hz, 2H), 2.99 (t, J=6.6 Hz, 2H),2.15-2.07 (m, 2H), 2.05-1.94 (m, 2H), 1.71-1.55 (m, 3H), 1.48-1.38 (m,1H).

Example 1.184 Synthesis ofN-tert-butyl-2-{methyl[2-(pyridazin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 175)

Compound 175 was synthesized similar to Compound 24 by replacing4-methyl-2-(trimethylstannyl)pyridine with3-(tributylstannyl)pyridazine. LCMS (ES) [M+1]⁺ m/z: 341, ¹H-NMR (300MHz, DMSO-d6) δ 10.00 (dd, J=2.3, 1.3 Hz, 1H), 9.36 (dd, J=5.3, 1.3 Hz,1H), 8.37 (dd, J=5.3, 2.3 Hz, 1H), 7.77 (s, 1H), 4.15 (s, 2H), 3.32 (s,3H), 3.18 (t, J=7.3 Hz, 2H), 2.85 (t, J=7.9 Hz, 2H), 2.15-1.82 (m, 2H),1.25 (s, 9H).

Example 1.185 Synthesis ofN-tert-butyl-2-[methyl(2-{1H-pyrazolo[4,3-c]pyridin-6-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 176)

Compound 176 was synthesized similar to Compound 24 by replacing4-methyl-2-(trimethylstannyl)pyridine with6-(trimethylstannyl)-1H-pyrazolo[4,3-c]pyridine. LCMS (ES) [M+1]⁺ m/z:380.2. ¹H NMR (300 MHz, DMSO-d6, ppm): 9.16 (s, 1H), 8.45 (s, 1H), 8.33(s, 1H), 7.69 (s, 1H), 4.18 (s, 2H), 3.26 (s, 3H), 3.13 (t, J=7.2 Hz,2H), 2.84 (t, J=7.9 Hz, 2H), 2.06-1.93 (m, 2H), 1.25 (s, 9H).

Example 1.186 Synthesis of2-[methyl({2-[4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]-N-(1-methyl-1H-pyrazol-4-yl)acetamide(Compound 178)

Compound 178 was synthesized similar to Compound 135 by replacingoxolan-3-amine with 5-pyrimidinamine. LCMS (ES) [M+1]⁺ m/z: 392. ¹H NMR(300 MHz, DMSO-d₆) δ 10.69 (s, 1H), 9.00 (s, 2H), 8.87 (s, 1H), 8.42 (d,J=5.4 Hz, 1H), 7.74 (d, J=2.4 Hz, 1H), 7.00 (dd, J=5.4, 2.4 Hz, 1H),4.45 (s, 2H), 3.78 (s, 3H), 3.39 (s, 3H), 3.22 (t, J=7.5 Hz, 2H), 2.84(t, J=7.8 Hz, 2H), 2.10-1.95 (m, 2H).

Example 1.187 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(1-methylcyclopentyl)acetamide(Compound 179)

Compound 179 was synthesized similar to Compound 144 by replacingcyclohexylamine with 1-methylcyclopentan-1-amine hydrochloride. LCMS(ES) [M+1]⁺ m/z: 426.3. ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (d, J=5.4 Hz,1H), 7.84 (d, J=2.4 Hz, 1H), 7.74 (s, 1H), 7.04 (dd, J=5.4, 2.4 Hz, 1H),4.93 (br, 1H), 4.21-4.09 (m, 4H), 3.76 (t, J=4.8 Hz, 2H), 3.26 (s, 3H),3.14 (t, J=7.5 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.07-1.89 (m, 4H),1.60-1.40 (m, 6H), 1.28 (s, 3H).

Example 1.188 Synthesis ofN-tert-butyl-2-{[2-(3-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 180)

Compound 180 was synthesized similar to Compound 24 by replacing4-methyl-2-(trimethylstannyl)pyridine with3-methoxy-2-(trimethylstannyl)pyridine. LCMS (ES) [M+1]⁺ m/z: 370. ¹HNMR (300 MHz, DMSO-d₆) δ 8.12 (dd, J=4.6, 1.3 Hz, 1H), 7.55-7.36 (m,3H), 4.09 (s, 2H), 3.74 (s, 3H), 3.15-3.07 (m, 5H), 2.74 (t, J=7.8 Hz,2H), 2.06-1.87 (m, 2H), 1.22 (s, 9H).

Example 1.189 Synthesis ofN-tert-butyl-2-{[2-(3-hydroxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 181)

Into a 50-mL round-bottom flask were placedN-tert-butyl-2-[[2-(3-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamide(50 mg, 0.135 mmol, 1.00 equiv), DCE (5 mL) and AlCl₃ (54 mg, 0.406mmol, 3.00 equiv). The resulting solution was stirred for 7 h at 65° C.The resulting mixture was concentrated under vacuum. The residue wasdissolved in 4 mL of MeOH and purified by Prep-HPLC with the followingconditions (Waters I): Column, Xbridge Prep C18 OBD column, 5 um, 19*150mm; mobile phase, Water (0.05% FA) and CH₃CN (5% CH3CN up to 35% in 15min); Detector, UV 254 nm. This resulted in 17.1 mg (35.6%) ofN-tert-butyl-2-[[2-(3-hydroxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamideas a white solid. LCMS (ES) [M+1]⁺ m/z 356. ¹H NMR (300 MHz, DMSO-d6) δ14.21 (s, 1H), 8.31-8.13 (m, 1H), 7.88-7.69 (m, 1H), 7.38-7.31 (m, 2H),4.21 (s, 2H), 3.25 (s, 3H), 3.21-3.09 (m, 2H), 2.99-2.81 (m, 2H),2.11-1.89 (m, 2H), 1.25 (s, 9H).

Example 1.190 Synthesis ofN-tert-butyl-2-{[2-(1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 182)

Compound 182 was synthesized similar to Compound 24 by replacing4-methyl-2-(trimethylstannyl)pyridine with1-(triphenylmethyl)imidazol-4-ylboronic acid. LCMS (ES) [M+1]⁺ m/z: 329;¹H NMR (300 MHz, DMSO-d6) δ 12.44 (br, 1H), 7.67 (s, 1H), 7.61 (s, 1H),7.55 (s, 1H), 4.12 (s, 2H), 3.25 (s, 3H), 3.09 (t, J=7.4 Hz, 2H), 2.76(t, J=7.8 Hz, 2H), 2.15-1.77 (m, 2H), 1.24 (s, 9H).

Example 1.191 Synthesis of(2R)—N-tert-butyl-2-[methyl(2-{1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]propanamide(Compound 183)

Compound 183 was synthesized similar to Compound 101 by replacing4-methoxy-2-(trimethylstannyl)pyridine with5-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridine. LCMS (ES) [M+1]⁺ m/z:394.2; ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 13.75 (s, 1H), 9.12 (s, 1H),8.85 (d, J=1.3 Hz, 1H), 8.30 (d, J=0.9 Hz, 1H), 7.92 (s, 1H), 5.17 (q,J=7.0 Hz, 1H), 3.22 (dt, J=15.6, 7.9 Hz, 1H), 3.16-3.08 (m, 4H),2.99-2.72 (m, 2H), 2.11-1.88 (m, 2H), 1.34 (d, J=7.1 Hz, 3H), 1.20 (s,9H).

Example 1.192 Synthesis of2-[methyl(2-{1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]-N-(1-methylcyclopentyl)acetamide(Compound 184)

Compound 184 was synthesized similar to Compound 135 by replacingoxolan-3-amine with 1-methylcyclopentan-1-amine hydrochloride and byreplacing 4-methoxy-2-(trimethylstannyl)pyridine with5-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridine. LCMS (ES) [M+1]⁺ m/z:406.2; ¹HNMR (300 MHz, DMSO-d₆, ppm) δ 13.40 (s, 1H), 9.09 (d, J=1.1 Hz,1H), 8.80 (d, J=1.3 Hz, 1H), 8.26 (d, J=0.9 Hz, 1H), 7.82 (s, 1H), 4.17(s, 2H), 3.30 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H),2.09-1.97 (m, 4H), 1.48 (dt, J=16.7, 7.2 Hz, 6H), 1.28 (s, 3H).

Example 1.193 Synthesis of2-[methyl(2-{1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]-N-(3-methyloxolan-3-yl)acetamide(Compound 185)

Compound 185 was synthesized similar to Compound 135 by replacingoxolan-3-amine with 3-methyloxolan-3-amine and by replacing4-methoxy-2-(trimethylstannyl)pyridine with5-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridine. LCMS (ES) [M+1]⁺ m/z:408.2; ¹H NMR (300 MHz, DMSO-d₆, ppm) δ13.71 (br, 1H), 9.09 (s, 1H),8.78 (d, J=1.3 Hz, 1H), 8.26 (d, J=7.9 Hz, 2H), 4.19 (s, 2H), 3.82 (d,J=8.7 Hz, 1H), 3.77-3.66 (m, 2H), 3.49 (d, J=8.7 Hz, 1H), 3.31 (s, 3H),3.15 (t, J=7.4 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.25 (dt, J=12.9, 6.5Hz, 1H), 2.01 (h, J=8.1, 7.5 Hz, 2H), 1.80 (dt, J=12.5, 7.6 Hz, 1H),1.32 (s, 3H).

Example 1.194 Synthesis ofN-(2-methoxypyrimidin-5-yl)-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 186)

Compound 186 was synthesized similar to Compound 142 by replacingcyclohexylamine with 2-methoxypyrimidin-5-amine. LCMS (ES) [M+1]⁺ m/z:395; ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 10.49 (s, 1H), 8.79 (s, 2H),7.69 (d, J=1.2 Hz, 1H), 7.61 (d, J=1.2 Hz, 1H), 4.37 (s, 2H), 3.87 (s,3H), 3.66 (s, 3H), 3.32 (s, 3H), 3.12 (t, J=7.2 Hz, 2H), 2.74 (t, J=7.8Hz, 2H), 2.00-1.90 (m, 2H).

Example 1.195 Synthesis of1-(4-methoxyphenyl)-4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepan-2-one(Compound 188)

To a solution of 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine(200 mg; 1.06 mmol; 1 eq.) in acetonitrile (3.5 ml) was added1,4-Diazepan-2-one hydrochloride (191 mg; 1.27 mmol; 1.2 eq.) andHunig's base (0.74 mL; 4.23 mmol; 4 eq.). The reaction was stirred at70° C. for 24 h. The reaction was evaporated, and the residue waspurified by silica gel chromatography (methanol/dichloromethanegradient) to give4-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}-1,4-diazepan-2-one(279 mg, 98%) as a white solid. LCMS (ES+): [M+H]⁺=266.9.

Step 2

4-{2-Chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}-1,4-diazepan-2-one(279 mg; 1.05 mmol; 1 eq.) was suspended in 1,4-dioxane (4 ml) and themixture was purged with Argon gas. 2-(Tributylstannyl)pyridine (0.68 mL;2.09 mmol; 2 eq.) and tetrakis(triphenylphosphane) palladium (121 mg;0.1 mmol; 0.1 eq.) were added and the reaction was stirred in a heatblock at 108° C. for 18 h. The reaction mixture was evaporated andpurified by reverse phase chromatography (C18, acetonitrile/0.1%HCOOH-water gradient) to give4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepan-2-one(66 mg) as a white solid. LCMS (ES+): [M+H]⁺=310.0.

Step 3

4-[2-(Pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepan-2-one(59 mg; 0.19 mmol; 1 eq.), 1-iodo-4-methoxybenzene (54 mg; 0.23 mmol;1.2 eq.), 1-N,2-N-dimethylcyclohexane-1,2-diamine (13.5 mg; 0.1 mmol;0.5 eq.), potassium phosphate tribasic (121 mg; 0.57 mmol; 3 eq.) weresuspended in 1,4-dioxane (3.5 ml). The mixture was purged with Argongas. Copper(I) iodide (12.7 mg; 0.07 mmol; 0.35 eq.) was added, thevessel was sealed and stirred in a heat block at 120° C. for 48 h. Thereaction was cooled, filtered, evaporated and the residue was purifiedby reverse phase chromatography (Waters XSelect CSH C18 column, 0-100%acetonitrile/0.1% aqueous formic acid gradient) to give1-(4-methoxyphenyl)-4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepan-2-one(33 mg, 42%) as a brown solid. LCMS (ES+): [M+H]⁺=416.1. ¹H NMR (400MHz, DMSO-d₆, 80° C.) δ 7.18-6.65 (m, 8H), 4.43-4.11 (m, 2H), 3.87-3.54(m, 11H), 2.15-1.96 (m, 4H).

Example 1.196 Synthesis ofN-(4-fluorophenyl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 189)

Compound 189 was synthesized similar to Compound 135 by replacingoxolan-3-amine with 4-fluoroaniline. LCMS (ES) [M+1]⁺ m/z: 408. ¹H NMR(300 MHz, DMSO-d₆) δ 10.34 (s, 1H), 8.45 (d, J=5.4 Hz, 1H), 7.79 (d,J=2.7 Hz, 1H), 7.72-7.47 (m, 2H), 7.16-7.10 (m, 2H), 7.00 (dd, J=5.7,2.7 Hz, 1H), 4.42 (s, 2H), 3.77 (s, 3H), 3.37 (s, 3H), 3.21 (t, J=7.2Hz, 2H), 2.84 (t, J=7.8 Hz, 2H), 2.08-1.95 (m, 2H).

Example 1.197 Synthesis ofN-(5-methoxypyridin-2-yl)-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 190)

Compound 190 was synthesized similar to Compound 142 by replacingcyclohexylamine with 4-methoxypyridin-2-amine. LCMS (ES) [M+1]⁺ m/z:394; ¹H NMR: (300 MHz, DMSO-d₆, ppm): δ 10.51 (s, 1H), 8.06 (d, J=2.7Hz, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.55 (d, J=1.2Hz, 1H), 7.41 (dd, J=9.0, 3.0 Hz, 1H), 4.43 (s, 2H), 3.80 (s, 3H), 3.62(s, 3H), 3.30 (s, 3H), 3.12 (t, J=7.2 Hz, 2H), 2.74 (t, J=7.8 Hz, 2H),2.00-1.90 (m, 2H).

Example 1.198 Synthesis ofN-tert-butyl-2-({2-[4-(2-hydroxyethoxy)-5-methylpyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 191)

Compound 191 was synthesized similar to Compound 44 by replacing2-chloropyridin-4-ol with 2-chloro-5-methylpyridin-4-ol. LCMS (ES)[M+1]⁺ m/z: 414. ¹H NMR (300 MHz, DMSO-d₆) δ 8.31 (s, 1H), 7.85 (s, 1H),7.65 (s, 1H), 4.93 (t, J=5.5 Hz, 1H), 4.20-4.17 (m, 4H), 3.83-3.78 (m,2H), 3.25 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.20(s, 3H), 2.11-1.93 (m, 2H), 1.23 (s, 9H).

Example 1.199 Synthesis ofN-tert-butyl-2-{[2-(4-methoxy-5-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 192)

Compound 192 was synthesized similar to Compound 24 by replacing4-methyl-2-(trimethylstannyl)pyridine with4-methoxy-5-methyl-2-(trimethylstannyl)pyridine. LCMS (ES) [M+1]⁺ m/z:384. ¹H NMR (300 MHz, DMSO-d₆) δ 8.31 (s, 1H), 7.88 (s, 1H), 7.65 (s,1H), 4.17 (s, 2H), 3.96 (s, 3H), 3.26 (s, 3H), 3.14 (t, J=7.4 Hz, 2H),2.82 (t, J=7.8 Hz, 2H), 2.18 (s, 3H), 2.04-1.94 (m, 2H), 1.23 (s, 9H).

Example 1.200 and Example 1.201 Synthesis ofN-tert-butyl-2-{[2-(1-ethyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 193) andN-tert-butyl-2-{[2-(1-ethyl-1H-imidazol-5-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 194)

A solution ofN-tert-butyl-2-[[2-(3H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamide(300.00 mg, 0.913 mmol, 1.00 equiv), K₂CO₃ (252.49 mg, 1.827 mmol, 2equiv) and bromoethane (149.30 mg, 1.370 mmol, 1.50 equiv) in DMF (5.00mL) was stirred for 2 h at 50° C. under air atmosphere. The crudeproduct was purified by Prep-HPLC to affordN-tert-butyl-2-[[2-(3-ethylimidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamide(Compound 192, 86 mg, 26.41%) andN-tert-butyl-2-[[2-(1-ethylimidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamide(Compound 193, 102 mg, 31.32%) as a white solid.

Compound 193: LCMS (ES) [M+1]⁺ m/z: 357; ¹H NMR (300 MHz, DMSO-d₆) δ7.80 (d, J=1.4 Hz, 1H), 7.66 (d, J=1.4 Hz, 1H), 7.64 (br, 1H), 4.09 (s,2H), 4.03 (q, J=7.3 Hz, 2H), 3.22 (s, 3H), 3.08 (t, J=7.2 Hz, 2H), 2.73(t, J=7.8 Hz, 2H), 2.05-1.86 (m, 2H), 1.39 (t, J=7.3 Hz, 3H), 1.25 (s,9H).

Compound 194: LCMS (ES) [M+1]⁺ m/z: 357; ¹H NMR (300 MHz, DMSO-d₆) δ7.75 (d, J=1.3 Hz, 1H), 7.61 (d, J=1.2 Hz, 1H), 7.58 (br, 1H), 4.53 (q,J=7.1 Hz, 2H), 4.11 (s, 2H), 3.19 (s, 3H), 3.08 (t, J=7.3 Hz, 2H), 2.75(t, J=7.8 Hz, 2H), 2.03-1.82 (m, 2H), 1.31 (t, J=7.1 Hz, 3H), 1.24 (s,9H).

Example 1.202 and Example 1.203 Synthesis ofN-tert-butyl-2-({2-[1-(2-hydroxyethyl)-1H-imidazol-4-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 195) andN-tert-butyl-2-({2-[1-(2-hydroxyethyl)-1H-imidazol-5-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 196)

Compound 195 and Compound 196 were synthesized similar to Compound 193and Compound 194 by replacing bromoethane with 2-(2-iodoethoxy)oxane.

Compound 195: LCMS (ES) [M+1]⁺ m/z: 373; ¹H NMR (300 MHz, DMSO-d₆) δ7.77(d, J=1.4 Hz, 1H), 7.62 (br, 1H), 7.61 (d, J=1.4 Hz, 1H), 5.00 (t, J=4.5Hz, 1H), 4.10 (s, 2H), 4.03 (t, J=5.4 Hz, 2H), 3.69 (q, J=5.1 Hz, 2H),3.20 (s, 3H), 3.06 (t, J=7.3 Hz, 2H), 2.73 (t, J=7.8 Hz, 2H), 2.02-1.79(m, 2H), 1.25 (s, 9H).

Compound 196: LCMS (ES) [M+1]⁺ m/z: 373; ¹H NMR (300 MHz, DMSO-d₆) δ7.66(d, J=1.2 Hz, 1H), 7.62 (d, J=1.2 Hz, 1H), 7.57 (s, 1H), 4.89 (t, J=5.3Hz, 1H), 4.56 (t, J=5.5 Hz, 2H), 4.09 (s, 2H), 3.67 (d, J=5.3 Hz, 2H),3.18 (s, 3H), 3.08 (t, J=7.3 Hz, 2H), 2.75 (t, J=7.8 Hz, 2H), 2.00-1.90(m, 2H), 1.26 (s, 9H).

Example 1.204 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(2-methoxypyrimidin-5-yl)acetamide(Compound 197)

Compound 197 was synthesized similar to Compound 144 by replacingcyclohexylamine with 2-methoxypyrimidin-5-amine. LCMS (ES) [M+1]⁺ m/z:452. ¹H NMR (300 MHz, DMSO-d₆) δ 10.51 (s, 1H), 8.77 (s, 2H), 8.44-8.42(d, J=5.6 Hz, 1H), 7.77-7.76 (d, J=2.5 Hz, 1H), 7.03-7.01 (dd, J=5.6,2.6 Hz, 1H), 4.92 (t, J=5.4 Hz, 1H), 4.42 (br, 2H), 4.05 (t, J=4.9 Hz,2H), 3.88 (s, 3H), 3.70 (q, J=5.1 Hz, 2H), 3.38 (s, 3H), 3.21 (t, J=7.2Hz, 2H), 2.83 (t, J=7.9 Hz, 2H), 2.10-2.00 (m, 2H).

Example 1.205 Synthesis ofN-(4-fluorophenyl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 198)

Compound 198 was synthesized similar to Compound 144 by replacingcyclohexylamine with 4-fluoroaniline. LCMS (ES) [M+1]⁺ m/z: 438. ¹H NMR(300 MHz, DMSO-d₆) δ 10.28 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 7.78 (d,J=2.5 Hz, 1H), 7.60 (dd, J=9.1, 5.1 Hz, 2H), 7.12 (t, J=8.9 Hz, 2H),7.00 (dd, J=5.6, 2.6 Hz, 1H), 4.90 (s, 1H), 4.41 (s, 2H), 4.02 (t, J=4.8Hz, 2H), 3.67 (t, J=4.8 Hz, 2H), 3.36 (s, 3H), 3.21 (t, J=7.3 Hz, 2H),2.83 (t, J=7.9 Hz, 2H), 2.08-1.95 (m, 2H).

Example 1.206 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methylpyridin-3-yl)acetamide(Compound 199)

Compound 199 was synthesized similar to Compound 144 by replacingcyclohexylamine with 6-methylpyridin-3-amine. LCMS (ES) [M+1]⁺ m/z: 435.¹H NMR (300 MHz, DMSO-d₆) δ 10.37 (s, 1H), 8.62 (d, J=2.5 Hz, 1H), 8.43(d, J=5.6 Hz, 1H), 7.91 (dd, J=8.4, 2.6 Hz, 1H), 7.77 (d, J=2.5 Hz, 1H),7.18 (d, J=8.4 Hz, 1H), 7.01 (dd, J=5.7, 2.6 Hz, 1H), 5.02 (t, J=5.5 Hz,1H), 4.42 (s, 2H), 4.03 (t, J=4.8 Hz, 2H), 3.69 (q, J=5.1 Hz, 2H), 3.38(s, 3H), 3.21 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.40 (s, 3H),2.08-2.01 (m, 2H).

Example 1.207 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6-methylpyridin-3-yl)acetamide(Compound 200)

Compound 200 was synthesized similar to Compound 135 by replacingoxolan-3-amine with 6-methylpyridin-3-amine. LCMS (ES) [M+1]⁺ m/z: 405.¹H NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.44(d, J=5.7 Hz, 1H), 7.89 (dd, J=8.4, 2.7 Hz, 1H), 7.78 (d, J=2.1 Hz, 1H),7.17 (d, J=8.4 Hz, 1H), 7.00 (dd, J=5.7, 2.7 Hz, 1H), 4.43 (s, 2H), 3.78(s, 3H), 3.37 (s, 3H), 3.21 (t, J=7.2 Hz, 2H), 2.84 (t, J=7.8 Hz, 2H),2.40 (s, 3H), 2.11-1.96 (m, 2H).

Example 1.208 Synthesis ofN-(6-methoxypyridin-3-yl)-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 201)

Compound 201 was synthesized similar to Compound 142 by replacingcyclohexylamine with 5-amino-2-methoxypyridine. LCMS (ES) [M+1]⁺ m/z:394; ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 10.27 (s, 1H), 8.38 (d, J=2.7Hz, 1H), 7.92 (dd, J=8.7, 2.7 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H), 7.60 (d,J=1.2 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 4.35 (s, 2H), 3.80 (s, 3H), 3.64(s, 3H), 3.31 (s, 3H), 3.13 (t, J=7.2 Hz, 2H), 2.74 (t, J=7.8 Hz, 2H),2.00-1.90 (m, 2H).

Example 1.209 Synthesis ofN-(4-fluorophenyl)-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 202)

Compound 202 was synthesized similar to Compound 142 by replacingcyclohexylamine with 4-fluoroaniline. LCMS (ES) [M+1]⁺ m/z: 381; ¹H-NMR:(300 MHz, DMSO-d₆, ppm): δ 10.28 (s, 1H), 7.70-7.60 (m, 4H), 7.17-7.11(m, 2H), 4.35 (s, 2H), 3.63 (s, 3H), 3.31 (s, 3H), 3.12 (t, J=7.2 Hz,2H), 2.74 (t, J=7.8 Hz, 2H), 2.00-1.90 (m, 2H).

Example 1.210 Synthesis of4-(4-methoxyphenyl)-1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepan-5-one(Compound 203)

Compound 203 was synthesized similar to Compound 188 by replacing1,4-diazepan-2-one hydrochloride with 1,4-diazepan-5-one hydrochloride.LCMS (ES+): [M+H]⁺=416.1. ¹H NMR (400 MHz, Methanol-d₄) δ 7.16-6.73 (m,8H), 4.29-3.76 (m, 11H), 3.06-2.85 (m, 6H).

Example 1.211 Synthesis of(2R)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(1-methylcyclopropyl)propanamide(Compound 204)

Compound 204 was synthesized similar to Compound 108 by replacingcyclohexylamine with 1-methylcyclopropan-1-amine. LCMS (ES+):[M+H]⁺=352.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.78-8.71 (m, 1H), 8.51 (s,1H), 8.43-8.35 (m, 1H), 8.06-7.96 (m, 1H), 7.59 (ddd, J=7.6, 4.7, 1.2Hz, 1H), 5.02 (q, J=7.0 Hz, 1H), 3.25-3.14 (m, 5H), 2.99-2.87 (m, 2H),2.14-1.93 (m, 2H), 1.37 (d, J=7.0 Hz, 3H), 1.17 (s, 3H), 0.61-0.41 (m,4H).

Example 1.212 Synthesis of(3S)-3-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-1-phenylpyrrolidin-2-one(Compound 205)

Compound 205 was synthesized similar to Compound 130 by replacing(2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid with(2S)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid andreplacing 2-(tributylstannyl)pyridine with4-methoxy-2-(tributylstannyl)pyridine. LCMS (ES+): [M+H]⁺=416.3. ¹H NMR(400 MHz, DMSO-d₆) δ 8.37 (d, J=5.6 Hz, 1H), 8.15 (s, 1H), 7.72 (d, 1H),7.70-7.66 (m, 2H), 7.40-7.34 (m, 2H), 7.17-7.12 (m, 1H), 6.97 (dd,J=5.6, 2.6 Hz, 1H), 5.49-5.31 (m, 1H), 3.99-3.86 (m, 2H), 3.78 (s, 3H),3.24-3.19 (m, 5H), 2.87-2.81 (m, 2H), 2.46-2.30 (m, 2H), 2.07-1.97 (m,2H).

Example 1.213 Synthesis of(3S)-1-(4-fluorophenyl)-3-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}pyrrolidin-2-one(Compound 206)

Compound 206 was synthesized similar to Compound 130 by replacing(2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid with(2S)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid andreplacing aniline with 4-fluoroaniline. LCMS (ES+): [M+H]⁺=404.2. ¹H NMR(400 MHz, DMSO-d₆) δ 8.54 (d, J=4.7 Hz, 1H), 8.15 (d, J=2.5 Hz, 1H),7.73 (dd, J=9.0, 4.9 Hz, 2H), 7.68-7.56 (m, 1H), 7.39-7.33 (m, 1H),7.26-7.18 (m, 2H), 5.29 (s, 1H), 3.99-3.84 (m, 2H), 3.25-3.21 (m, 5H),2.88-2.80 (m, 2H), 2.46-2.27 (m, 2H), 2.06-1.96 (m, 2H).

Example 1.214 Synthesis of(3S)-3-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-1-(1-methylcyclopentyl)pyrrolidin-2-one(Compound 207)

Compound 207 was synthesized similar to Compound 130 by replacing(2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid with(2S)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid andreplacing aniline with 1-methylcyclopentan-1-aminium chloride. LCMS(ES+): [M+H]⁺=392.2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.77-8.56 (m, 1H), 8.25(d, J=7.8 Hz, 1H), 7.95-7.79 (m, 1H), 7.51-7.34 (m, 1H), 5.36-5.12 (m,1H), 3.63-3.46 (m, 2H), 3.22-3.14 (m, 2H), 3.06 (s, 3H), 2.82 (t, J=8.0Hz, 2H), 2.33-2.22 (m, 1H), 2.14-1.93 (m, 5H), 1.78-1.54 (m, 6H), 1.21(s, 3H).

Example 1.215 Synthesis of(3S)-3-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-1-(pyridin-4-yl)pyrrolidin-2-one(Compound 208)

Compound 208 was synthesized similar to Compound 130 by replacing(2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid with(2S)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid andreplacing aniline with 4-pyridinamine. LCMS (ES+): [M+H]⁺=386.9. ¹H NMR(400 MHz, Methanol-d₄) δ 8.53 (d, J=4.9 Hz, 1H), 8.48-8.44 (m, 2H), 7.97(d, J=7.9 Hz, 1H), 7.84-7.78 (m, 2H), 7.49-7.42 (m, 1H), 7.35-7.29 (m,1H), 4.14-3.91 (m, 3H), 3.44 (s, 3H), 2.99-2.93 (m, 2H), 2.62-2.51 (m,2H), 2.17-2.11 (m, 2H).

Example 1.216 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(5-methoxypyridin-2-yl)acetamide(Compound 209)

Compound 209 was synthesized similar to Compound 144 by replacingcyclohexylamine with 5-methoxyl-2-aminopyridine. LCMS (ES) [M+1]⁺ m/z:451. ¹H NMR (300 MHz, DMSO-d₆) δ 10.54 (s, 1H), 8.44-8.42 (d, J=5.6 Hz,1H), 8.04-8.03 (d, J=3.0 Hz, 1H), 7.98-7.95 (d, J=9.1 Hz, 1H), 7.77-7.76(d, J=2.5 Hz, 1H), 7.42-7.38 (dd, J=9.1, 3.0 Hz, 1H), 6.99-6.96 (dd,J=5.6, 2.7 Hz, 1H), 4.90-4.87 (t, J=5.4 Hz, 1H), 4.50 (s, 2H), 4.02-3.96(q, J=7.4 Hz, 2H), 3.80 (s, 3H), 3.69-3.64 (q, J=5.4 Hz, 2H), 3.34 (s,3H), 3.22-3.17 (t, J=7.3 Hz, 2H), 2.85-2.80 (t, J=7.8 Hz, 2H), 2.05-1.98(m, 2H).

Example 1.217 Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide(Compound 210)

Step 1

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen were placed1-[(2-chloropyridin-4-yl)oxy]-2-methylpropan-2-ol (1.00 g, 4.96 mmol,1.00 equiv), Toluene (30 mL), Sn₂Me₆ (1.71 g, 5.22 mmol, 1.05 equiv) andPd(PPh₃)₄ (0.57 g, 0.49 mmol, 0.10 equiv). The resulting solution wasstirred for 2 h at 100° C. To this mixture was added ethyl2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetate(0.94 g, 3.48 mmol, 0.70 equiv) and Pd(PPh₃)₄ (0.57 g, 0.49 mmol, 0.10equiv). The resulting solution was stirred overnight at 100° C. Aftercooled to ambient temperature the resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withdichloromethane/methanol (20:1). This resulted in 300 mg (15.11%) ofethyl2-([2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetateas brown oil. LCMS (ES) [M+1]⁺ m/z 401.

Step 2

Into a 50-mL round-bottom flask were placed ethyl2-([2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetate(300 mg, 0.75 mmol, 1.00 equiv) and MeOH (3 mL). This was followed bythe addition of a solution of LiOH (36 mg, 1.50 mmol, 2.00 equiv) in H₂O(1 mL) dropwise with stirring at 25° C. The resulting solution wasstirred for 2 hr at 25° C. and concentrated under vacuum. The resultingsolution was extracted with 2×20 mL of dichloromethane and the aqueouswas separated and concentrated under vacuum. This resulted in 150 mg(52.92%) of lithio2-([2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetateas a brown solid. LCMS (ES) [M−Li+H+1]⁺ m/z 373.

Step 3

To a stirred solution of([2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)aceticacid (200.00 mg, 0.537 mmol, 1.00 equiv), 5-amino-2-methoxypyridine (80mg, 0.64 mmol, 1.2 equiv) and DIEA (138.8 mg, 1.07 mmol, 2.0 equiv) inDMF (3 mL) was added HATU (265.4 mg, 0.69 mmol, 1.3 equiv) in oneportion at 0° C. After stirred for 5 h at 0-25° C., the resultingmixture was purified by preparative HPLC (Column, C18; mobile phase A:CH₃CN, Mobile phase B: Water. Flow rate: 20 mL/min) to give2-[2-[(2S)-2-(2-formyl-3-hydroxyphenoxymethyl)piperidine-1-carbonyl]phenyl]acetamide(123.1 mg, 12.3%) as an off white solid. LCMS (ES) [M+1]⁺ m/z: 479. ¹HNMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.45 (d, J=5.6 Hz, 1H), 8.34 (d,J=2.6 Hz, 1H), 7.87 (dd, J=8.9, 2.7 Hz, 1H), 7.79 (d, J=2.6 Hz, 1H),7.03 (dd, J=5.7, 2.6 Hz, 1H), 6.77 (d, J=8.9 Hz, 1H), 4.67 (s, 1H), 4.41(s, 2H), 3.82-3.78 (m, 5H), 3.37 (s, 3H), 3.21 (t, J=7.3 Hz, 2H), 2.84(t, J=7.8 Hz, 2H), 2.04-1.99 (m, 2H), 1.17 (s, 6H).

Example 1.218 Synthesis ofN-tert-butyl-2-[methyl(2-{4-[(oxetan-3-yl)methoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 211)

Compound 211 was synthesized similar to Compound 24 replacing4-methyl-2-(tributylstannyl)-pyridine with4-(oxetan-3-ylmethoxy)-2-(tributylstannyl)pyridine. LCMS (ES+):[M+H]⁺=426.2. ¹H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J=5.8 Hz, 1H), 7.95(d, J=2.6 Hz, 1H), 7.82 (s, 1H), 7.29 (dd, J=5.9, 2.6 Hz, 1H), 4.77-4.69(m, 2H), 4.51-4.42 (m, 4H), 4.22 (s, 2H), 3.48-3.43 (m, 1H), 3.37 (s,3H), 3.22-3.17 (m, 2H), 2.96-2.87 (m, 2H), 2.09-1.98 (m, 2H), 1.24 (s,9H).

Example 1.219 Synthesis of(2R)—N-tert-butyl-2-({2-[4-(difluoromethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-4-(methylsulfanyl)butanamide(Compound 212)

Compound 212 was synthesized similar to Compound 114 by replacing(2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid with(2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid andby replacing 2-(tributylstannyl)pyridine with4-(difluoromethoxy)-2-(tributylstannyl)pyridine. LCMS (ES+):[M+H]⁺=480.4. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16-1.20 (m, 9H)1.89-2.15 (m, 7H) 2.34-2.46 (m, 2H) 2.74-2.95 (m, 2H) 3.00-3.14 (m, 4H)3.18-3.25 (m, 2H) 4.97-5.09 (m, 1H) 7.29 (dd, J=5.48, 2.35 Hz, 1H) 7.57(t, J=72.78 Hz, 1H) 7.81-7.87 (m, 1H) 8.09 (d, J=1.96 Hz, 1H) 8.68 (d,J=5.87 Hz, 1H).

Example 1.220 Synthesis of2-({2-[4-(difluoromethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(1-methyl-1H-pyrazol-4-yl)acetamide(Compound 213)

Compound 213 was synthesized similar to Compound 177 by replacing2-(tributylstannyl)-4-(2,2,2-trifluoroethoxy)pyridine with4-(difluoromethoxy)-2-(tributylstannyl)pyridine. LCMS (ES+):[M+H]⁺=429.9. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.04-2.16 (m, 2H) 3.04 (brt, J=7.83 Hz, 2H) 3.26-3.28 (m, 2H) 3.52 (s, 3H) 3.70-3.74 (m, 3H)4.61-4.69 (m, 2H) 6.32-6.38 (m, 1H) 6.36 (d, J=1.57 Hz, 1H) 7.42-7.47(m, 1H) 7.43-7.83 (m, 2H) 7.63 (t, J=73.17 Hz, 1H) 8.04-8.12 (m, 1H)8.77-8.85 (m, 1H) 10.78-10.86 (m, 1H).

Example 1.221 Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(5-methoxypyridin-2-yl)acetamide(Compound 214)

Compound 214 was synthesized similar to Compound 210 replacing5-amino-2-methoxypyridine with 5-methoxypyridin-2-amine. LCMS (ES)[M+1]⁺ m/z: 479.3. ¹H NMR (300 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.44 (d,J=5.6 Hz, 1H), 8.28 (s, 1H), 8.02 (d, J=3.1 Hz, 1H), 7.95 (d, J=9.1 Hz,1H), 7.76 (d, J=2.5 Hz, 1H), 7.39 (dd, J=9.1, 3.1 Hz, 1H), 7.00 (dd,J=5.7, 2.5 Hz, 1H), 4.51 (s, 2H), 3.81-3.76 (m, 5H), 3.34 (s, 3H), 3.19(t, J=7.3 Hz, 2H), 2.83 (t, J=7.9 Hz, 2H), 2.08-1.95 (m, 2H), 1.15 (s,6H).

Example 1.222 Synthesis of2-({2-[4-(cyclopropylmethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(1-methyl-1H-pyrazol-4-yl)acetamide(Compound 215)

Compound 215 was synthesized similar to Compound 177 replacing2-bromo-4-(2,2,2-trifluoroethoxy)pyridine with2-bromo-4-(cyclopropylmethoxy)pyridine. LCMS (ES) [M+1]⁺ m/z: 443.1. ¹HNMR (400 MHz, DMSO-d₆) δ 10.58 (s, 1H), 8.47 (d, J=5.8 Hz, 1H), 7.78 (d,J=2.6 Hz, 1H), 7.50 (d, J=2.2 Hz, 1H), 7.10 (dd, J=5.9, 2.6 Hz, 1H),6.34 (d, J=2.2 Hz, 1H), 4.46 (s, 2H), 3.92 (d, J=7.1 Hz, 2H), 3.71 (s,3H), 3.36 (s, 3H), 3.20 (d, J=14.8 Hz, 2H), 2.87 (t, J=7.9 Hz, 2H),2.09-1.94 (m, 2H), 1.21 (s, 1H), 0.63-0.52 (m, 2H), 0.40-0.29 (m, 2H).

Example 1.223 Synthesis of2-({2-[4-(difluoromethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-fluoropyridin-3-yl)acetamide(Compound 216)

Compound 216 was synthesized similar to Compound 24 replacing4-methyl-2-(tributylstannyl)-pyridine with4-(difluoromethoxy)-2-(tributylstannyl)pyridine and by replacingtert-butylamine with 6-fluoro-3-pyridinylamine. LCMS (ES+):[M+H]⁺=445.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.03-2.16 (m, 2H) 3.02 (brt, J=7.83 Hz, 2H) 3.26-3.29 (m, 2H) 3.53 (s, 2H) 4.62-4.70 (m, 2H)7.11-7.18 (m, 1H) 7.60 (t, J=71.99 Hz, 1H) 7.45-7.51 (m, 1H) 8.05 (br s,1H) 8.10-8.18 (m, 1H) 8.45 (br s, 1H) 8.73-8.81 (m, 1H) 10.80-10.89 (m,1H).

Example 1.224 Synthesis of2-({2-[4-(difluoromethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(5-methoxypyridin-2-yl)acetamide(Compound 217)

Compound 217 was synthesized similar to Compound 24 replacing4-methyl-2-(tributylstannyl)-pyridine with4-(difluoromethoxy)-2-(tributylstannyl)pyridine and by replacingtert-butylamine with 5-methoxypyridin-2-amine. LCMS (ES+): [M+H]⁺=456.9.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.04-2.13 (m, 2H) 3.00 (br t, J=7.83 Hz,2H) 3.28 (br d, J=7.04 Hz, 2H) 3.50 (s, 3H) 3.77-3.80 (m, 3H) 4.65-4.72(m, 2H) 7.39 (dd, J=9.00, 3.13 Hz, 1H) 7.41-7.80 (m, 1H) 7.46 (dd,J=5.48, 2.35 Hz, 1H) 7.87-7.96 (m, 1H) 8.03 (d, J=2.74 Hz, 1H) 8.04-8.08(m, 1H) 8.77 (d, J=5.87 Hz, 1H) 10.73-10.79 (m, 1H).

Example 1.225 Synthesis of2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(1-methyl-1H-pyrazol-4-yl)acetamide(Compound 218)

Compound 218 was synthesized similar to Compound 177 by replacing2-(tributylstannyl)-4-(2,2,2-trifluoroethoxy)pyridine with3-(tributylstannyl)isoquinoline. LCMS (ES+): [M+H]⁺=414.0. ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.08-2.19 (m, 2H) 3.10 (br t, J=7.83 Hz, 2H)3.30-3.36 (m, 2H) 3.61 (br s, 3H) 3.75-3.83 (m, 3H) 4.61-4.72 (m, 2H)6.32-6.42 (m, 1H) 7.45-7.54 (m, 1H) 7.86-7.95 (m, 1H) 7.95-8.08 (m, 2H)8.33 (br d, J=8.22 Hz, 1H) 8.79-8.98 (m, 1H) 9.52-9.62 (m, 1H)10.98-11.15 (m, 1H)

Example 1.226 Synthesis ofN-(6-methoxypyridin-3-yl)-2-[methyl(2-{1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 219)

Compound 219 was synthesized similar to Compound 135 by replacingoxolan-3-amine with 5-amino-2-methoxypyridine and by replacing4-methoxy-2-(trimethylstannyl)pyridine with5-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridine. LCMS (ES) [M+1]⁺ m/z:431.2; ¹HNMR (300 MHz, DMSO-d₆, ppm) δ 13.70 (s, 1H), 10.37 (s, 1H),9.06 (s, 1H), 8.70 (d, J=1.2 Hz, 1H), 8.41 (t, J=2.4 Hz, 1H), 8.09 (s,1H), 7.95 (ddd, J=8.9, 2.8, 1.5 Hz, 1H), 6.80 (d, J=8.9 Hz, 1H), 4.42(s, 2H), 3.80 (s, 3H), 3.39 (s, 3H), 3.20 (t, J=7.3 Hz, 2H), 2.84 (t,J=7.8 Hz, 2H), 2.11-1.93 (m, 2H).

Example 1.227 Synthesis ofN-(1-methyl-1H-pyrazol-4-yl)-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 220)

Compound 220 was synthesized similar to Compound 177 by replacing2-(tributylstannyl)-4-(2,2,2-trifluoroethoxy)pyridine with1-methyl-4-(tributylstannyl)-1H-imidazole. LCMS (ES) [M+1]⁺ m/z: 367.2;¹H NMR (400 MHz, dmso) δ 10.73 (s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 7.53(d, J=2.2 Hz, 1H), 6.35 (d, J=2.2 Hz, 1H), 4.58 (s, 3H), 4.55 (s, 2H),3.77 (s, 3H), 3.73 (s, 3H), 3.16 (s, 2H), 2.92 (t, J=7.9 Hz, 2H),2.09-1.96 (m, 2H).

Example 1.228 Synthesis ofN-(6-fluoropyridin-3-yl)-2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 221)

Compound 221 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with3-(tributylstannyl)isoquinoline and by replacing oxolan-3-amine with6-fluoro-3-pyridinylamine. LCMS (ES+): [M+H]⁺=429.2. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.99-2.08 (m, 2H) 2.84-2.91 (m, 2H) 3.20-3.26 (m, 2H)3.42 (s, 3H) 4.46-4.51 (m, 2H) 7.10-7.16 (m, 1H) 7.67-7.73 (m, 1H)7.73-7.79 (m, 1H) 7.81-7.86 (m, 1H) 8.13-8.17 (m, 1H) 8.17-8.24 (m, 1H)8.43-8.48 (m, 1H) 8.71-8.75 (m, 1H) 9.32-9.37 (m, 1H) 10.67-10.74 (m,1H)

Example 1.229 Synthesis of2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6-methylpyridin-3-yl)acetamide(Compound 222)

Compound 222 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with3-(tributylstannyl)isoquinoline and by replacing oxolan-3-amine with5-methyl-2-pyridinamine. LCMS (ES+): [M+H]⁺=425.2. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.09-2.19 (m, 2H) 2.52-2.60 (m, 3H) 3.11 (br t, J=7.83Hz, 2H) 3.35-3.37 (m, 2H) 3.64 (s, 3H) 4.84-4.97 (m, 2H) 7.66-7.75 (m,1H) 7.85-7.93 (m, 1H) 7.93-8.00 (m, 1H) 8.28-8.37 (m, 2H) 8.45-8.65 (m,1H) 9.02-9.10 (m, 1H) 9.18-9.28 (m, 1H) 9.51-9.60 (m, 1H) 12.14-12.47(m, 1H)

Example 1.230 Synthesis of2-{[2-(4-ethoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6-methoxypyridin-3-yl)acetamide(Compound 223)

Compound 223 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with in situ made4-ethoxy-2-(trimethylstannyl)pyridine and replacing oxolan-3-amine with5-amino-2-methoxypyridine. LCMS (ES) [M+1]⁺ m/z: 435. ¹H NMR (300 MHz,DMSO-d6) δ 10.28 (s, 1H), 8.46 (d, J=5.7 Hz, 1H), 8.35 (d, J=2.6 Hz,1H), 7.89 (dd, J=8.9, 2.7 Hz, 1H), 7.78 (d, J=2.6 Hz, 1H), 7.06 (dd,J=5.6, 2.6 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 4.42 (s, 2H), 4.06 (q, J=7.0Hz, 2H), 3.80 (s, 3H), 3.40 (s, 3H), 3.23 (t, J=7.3 Hz, 2H), 2.86 (t,J=7.7 Hz, 2H), 2.11-1.97 (m, 2H), 1.28 (t, J=6.9 Hz, 3H).

Example 1.231 Synthesis of2-({2-[4-(cyclopropylmethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide(Compound 224)

Compound 224 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with in situ made4-cyclopropylmethoxy-2-(trimethylstannyl)pyridine and replacingoxolan-3-amine with 5-amino-2-methoxypyridine. LCMS (ES) [M+1]⁺ m/z:461. ¹H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.42 (d, J=5.6 Hz, 1H),8.33 (d, J=2.7 Hz, 1H), 7.86 (dd, J=8.9, 2.7 Hz, 1H), 7.76 (d, J=2.5 Hz,1H), 6.98 (dd, J=5.6, 2.6 Hz, 1H), 6.77 (d, J=8.9 Hz, 1H), 4.39 (s, 2H),3.86 (d, J=7.1 Hz, 2H), 3.80 (s, 3H), 3.37 (s, 3H), 3.21 (t, J=7.2 Hz,2H), 2.83 (t, J=7.8 Hz, 2H), 2.10-1.911 (m, 2H), 1.38-1.09 (m, 1H), 0.56(q, J=5.5 Hz, 2H), 0.30 (d, J=5.2 Hz, 2H).

Example 1.232 Synthesis of2-({2-[4-(difluoromethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide(Compound 225)

Compound 225 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with in situ made4-(difluoromethoxy)-2-(trimethylstannyl)pyridine and replacingoxolan-3-amine with 5-amino-2-methoxypyridine. LCMS (ES) [M+1]⁺ m/z:457. ¹H NMR (300 MHz, DMSO-d6) δ 10.23 (br, 1H), 8.63 (d, J=5.7 Hz, 1H),8.35 (d, J=2.7 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.88 (dd, J=9.0, 2.7 Hz,1H), 7.49 (t, J=72.6 Hz 1H, CHF2), 7.26 (dd, J=5.7, 2.4 Hz, 1H), 6.75(d, J=9.0 Hz, 1H), 4.43 (s, 2H), 3.80 (s, 3H), 3.37 (s, 3H), 3.21 (t,J=7.5 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.07-1.96 (m, 2H).

Example 1.233 Synthesis ofN-tert-butyl-2-[(2-{2H-[1,3]dioxolo[4,5-c]pyridin-6-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 226)

Compound 226 was synthesized similar to Compound 24 by replacing4-methyl-2-(tributylstannyl)pyridine with6-(trimethylstannyl)-[1,3]dioxolo[4,5-c]pyridine. LCMS (ES) [M+1]⁺ m/z:384. ¹H NMR (300 MHz, DMSO-d₆) δ 8.20 (s, 1H), 7.95 (s, 1H), 7.71 (s,1H), 6.20 (s, 2H), 4.10 (s, 2H), 3.32 (s, 3H), 3.14 (t, J=7.4 Hz, 2H),2.79 (t, J=7.9 Hz, 2H), 2.05-1.89 (m, 2H), 1.25 (s, 9H).

Example 1.234 Synthesis of2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6-methoxypyridin-3-yl)acetamide(Compound 227)

Compound 227 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with3-(tributylstannyl)isoquinoline and replacing oxolan-3-amine with5-amino-2-methoxypyridine. LCMS (ES) [M+1]⁺ m/z: 457. ¹H NMR (300 MHz,DMSO-d6) δ 10.23 (br, 1H), 8.63 (d, J=5.7 Hz, 1H), 8.35 (d, J=2.7 Hz,1H), 7.98 (d, J=2.4 Hz, 1H), 7.88 (dd, J=9.0, 2.7 Hz, 1H), 7.49 (t,J=72.6 Hz 1H, CHF2), 7.26 (dd, J=5.7, 2.4 Hz, 1H), 6.75 (d, J=9.0 Hz,1H), 4.43 (s, 2H), 3.80 (s, 3H), 3.37 (s, 3H), 3.21 (t, J=7.5 Hz, 2H),2.82 (t, J=7.8 Hz, 2H), 2.07-1.96 (m, 2H).

Example 1.235 Synthesis of2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6-methoxypyridin-3-yl)acetamide(Compound 228)

Compound 228 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with3-(tributylstannyl)isoquinoline and replacing oxolan-3-amine with3-aminopyridine. LCMS (ES) [M+1]⁺ m/z: 411. ¹H NMR (300 MHz, DMSO-d6) δ9.48 (s, 1H), 9.28 (d, J=2.4 Hz, 1H), 9.14 (s, 1H), 8.82 (s, 1H), 8.52(s, 1H), 8.33-8.20 (m, 2H), 8.00 (t, J=7.1 Hz, 1H), 7.93-7.79 (m, 2H),4.90 (s, 2H), 3.57 (s, 3H), 3.38-3.19 (s, 2H), 3.18-2.99 (m, 2H),2.09-2.00 (m, 2H).

Example 1.236 Synthesis ofN-(6-methoxypyridin-3-yl)-2-[methyl({2-[4-(trifluoromethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide(Compound 229)

Compound 229 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with4-(trifluoromethoxy)-2-(trimethylstannyl)pyridine and replacingoxolan-3-amine with 5-amino-2-methoxypyridine. LCMS (ES) [M+1]⁺ m/z:475. ¹H NMR (300 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.75 (d, J=5.5 Hz, 1H),8.36 (t, J=2.2 Hz, 1H), 8.09 (d, J=2.37 Hz 1H), 7.87 (ddd, J=8.9, 2.8,1.3 Hz, 1H), 7.46 (dd, J=5.3, 2.1 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 4.41(s, 2H), 3.80 (s, 3H), 3.38 (s, 3H), 3.22 (t, J=7.3 Hz, 2H), 2.85 (t,J=7.8 Hz, 2H), 2.10-1.922 (m, 2H).

Example 1.237 Synthesis ofN-(6-methoxypyridin-3-yl)-2-[methyl({2-[4-(trifluoromethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide(Compound 230)

Compound 230 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with4-(trifluoromethoxy)-2-(trimethylstannyl)pyridine and replacingoxolan-3-amine with 5-amino-2-methoxypyridine. LCMS (ES) [M+1]⁺ m/z:475. ¹H NMR (300 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.75 (d, J=5.5 Hz, 1H),8.36 (t, J=2.2 Hz, 1H), 8.09 (d, J=2.37 Hz 1H), 7.87 (ddd, J=8.9, 2.8,1.3 Hz, 1H), 7.46 (dd, J=5.3, 2.1 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 4.41(s, 2H), 3.80 (s, 3H), 3.38 (s, 3H), 3.22 (t, J=7.3 Hz, 2H), 2.85 (t,J=7.8 Hz, 2H), 2.10-1.922 (m, 2H).

Example 1.238 Synthesis of2-[methyl({2-[4-(trifluoromethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]-N-(1-methyl-1H-pyrazol-4-yl)acetamide(Compound 231)

Compound 231 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with4-(trifluoromethoxy)-2-(trimethylstannyl)pyridine and replacingoxolan-3-amine with 1-methylpyrazol-4-amine. LCMS (ES) [M+1]⁺ m/z: 448.¹H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.78 (d, J=5.6 Hz, 1H), 8.10(d, J=2.3 Hz, 1H), 7.82 (s, 1H), 7.47 (dd, J=5.7, 1.4 Hz, 1H), 7.39 (s,1H), 4.36 (s, 2H), 3.75 (s, 3H), 3.28 (s, 3H), 3.26-3.13 (m, 2H), 2.85(t, J=7.8 Hz, 2H), 2.10-1.93 (m, 2H).

Example 1.239 Synthesis of2-[methyl(2-{1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]-N-(1-methyl-1H-pyrazol-3-yl)acetamide(Compound 232)

Compound 232 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with5-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridine and replacingoxolan-3-amine with 2-methylpyrimidin-5-amine. LCMS (ES) [M+1]⁺ m/z:404. ¹H NMR (300 MHz, DMSO-d6) δ13.67 (s, 1H), 10.68 (s, 1H), 9.08 (s,1H), 8.68 (d, J=1.4 Hz, 1H), 8.12 (s, 1H), 7.52 (d, J=2.3 Hz, 1H), 6.41(d, J=2.3 Hz, 1H), 4.41 (s, 2H), 3.76 (s, 3H), 3.38 (s, 3H), 3.18 (t,J=7.4 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.03-1.98 (m, 2H).

Example 1.240 Synthesis of2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(5-methoxypyridin-2-yl)acetamide(Compound 233)

Compound 233 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with3-(tributylstannyl)isoquinoline and replacing oxolan-3-amine with5-methoxypyridin-2-amine. LCMS (ES) [M+1]⁺ m/z: 441. ¹H NMR (300 MHz,DMSO-d6) δ 10.71 (s, 1H), 9.35 (s, 1H), 8.72 (s, 1H), 8.16 (0.4 HCOOH),8.14 (d, J=7.8 Hz, 1H), 8.10 (d, J=3.0 Hz, 1H), 7.99 (d, J=9.0 Hz, 1H),7.85-7.63 (m, 3H), 7.38 (dd, J=9.1, 3.1 Hz, 1H), 4.51 (s, 2H), 3.79 (s,3H), 3.41 (s, 3H), 3.22 (t, J=7.3 Hz, 2H), 2.87 (t, J=7.8 Hz, 2H),2.07-1.98 (m, 2H).

Example 1.241 Synthesis of2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-[6-(trifluoromethoxy)pyridin-3-yl]acetamide(Compound 234)

Compound 234 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with3-(tributylstannyl)isoquinoline and replacing oxolan-3-amine with6-(trifluoromethoxy)pyridin-3-amine. LCMS (ES) [M+1]⁺ m/z: 495. ¹H NMR(300 MHz, DMSO-d6) δ 11.51 (br, 1H), 9.56 (s, 1H), 9.10 (s, 1H), 8.70(s, 1H), 8.32 (d, J=8.1 Hz, 2H), 8.10 (s, 1H), 7.98-7.85 (m, 2H), 7.27(d, J=8.8 Hz, 1H), 4.83 (s, 2H), 3.63 (s, 3H), 3.37-3.22 (m, 2H), 3.11(t, J=8.0 Hz, 2H), 2.20-2.09 (m, 2H).

Example 1.242 Synthesis of2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(5-methylpyridin-3-yl)acetamide(Compound 235)

Compound 235 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with3-(tributylstannyl)isoquinoline and replacing oxolan-3-amine with5-methylpyridin-3-amine. LCMS (ES) [M+1]⁺ m/z: 425. ¹H NMR (300 MHz,DMSO-d6) δ 10.52 (s, 1H), 9.36 (s, 1H), 8.72 (s, 1H), 8.61 (d, J=2.4 Hz,1H), 8.20-8.11 (m, 2H), 8.08 (d, J=1.9 Hz, 1H), 7.92 (s, 1H), 7.85-7.64(m, 3H), 4.48 (s, 2H), 3.43 (s, 3H), 3.24 (s, 2H), 2.88 (t, J=7.8 Hz,2H), 2.21 (s, 3H), 2.07-2.01 (m, 2H).

Example 1.243 Synthesis of2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(1-methyl-1H-imidazol-4-yl)acetamide(Compound 236)

Compound 236 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with3-(tributylstannyl)isoquinoline and replacing oxolan-3-amine with1-methylimidazol-4-amine. LCMS (ES) [M+1]⁺ m/z: 414.3. ¹H NMR (300 MHz,DMSO-d6) δ 10.61 (s, 1H), 9.37 (d, J=3.1 Hz, 1H), 8.71 (d, J=2.9 Hz,1H), 8.15 (dd, J=8.1, 3.1 Hz, 1H), 7.95-7.86 (m, 1H), 7.82-7.64 (m, 2H),7.41 (t, J=2.1 Hz, 1H), 7.20-7.11 (m, 1H), 4.44 (s, 2H), 3.57 (s, 3H),3.38 (s, 3H), 3.19 (t, J=7.4 Hz, 2H), 2.86 (d, J=7.7 Hz, 2H), 2.05-2.01(m, 2H).

Example 1.244 Synthesis of2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(1-methyl-1H-pyrazol-3-yl)acetamide(Compound 237)

Compound 237 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with3-(tributylstannyl)isoquinoline and replacing oxolan-3-amine with1-methylpyrazol-3-amine. LCMS (ES) [M+1]⁺ m/z: 414. ¹H NMR (300 MHz,DMSO-d6) δ 10.75 (s, 1H), 9.37 (s, 1H), 8.69 (s, 1H), 8.15 (d, J=8.3 Hz,1H), 7.88 (d, J=8.1 Hz, 1H), 7.83-7.74 (m, 1H), 7.74-7.66 (m, 1H), 7.52(d, J=2.3 Hz, 1H), 6.42 (d, J=2.2 Hz, 1H), 4.42 (s, 2H), 3.77 (s, 3H),3.40 (s, 3H), 3.21 (t, J=7.2 Hz, 2H), 2.86 (t, J=7.8 Hz, 2H), 2.08-2.00(m, 2H).

Example 1.245 Synthesis of2-({2-[4-(2-methoxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide(Compound 238)

Compound 238 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with4-(2-methoxyethoxy)-2-(trimethylstannyl)pyridine and replacingoxolan-3-amine with 5-amino-2-methoxypyridine. LCMS (ES) [M+1]⁺ m/z:465. ¹H NMR (300 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.46 (d, J=5.7 Hz, 1H),8.35 (d, J=2.7 Hz, 1H), 8.14 (s, HCOOH), 7.89 (dd, J=9.0, 2.7 Hz, 1H),7.79 (d, J=2.7 Hz, 1H), 7.05 (dd, J=5.7, 2.7 Hz, 1H), 6.78 (d, J=9.0 Hz,1H), 4.42 (s, 2H), 4.16-4.09 (m, 2H), 3.81 (s, 3H), 3.62-3.60 (m, 2H),3.39 (s, 3H), 3.29 (s, 3H), 3.22 (t, J=7.2 Hz, 2H), 2.85 (t, J=7.8 Hz,2H), 2.07-1.96 (m, 2H).

Example 1.246 Synthesis ofN-tert-butyl-2-({2-[4-(2-methoxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 239)

Compound 239 was synthesized similar to Compound 24 by replacing4-methyl-2-(trimethylstannyl)pyridine with4-(2-methoxyethoxy)-2-(trimethylstannyl)pyridine. LCMS (ES) [M+1]⁺ m/z:414. ¹H NMR (300 MHz, DMSO-d6) δ 8.48 (d, J=5.7 Hz, 1H), 8.14 (s,HCOOH), 7.86 (d, J=2.4 Hz, 1H), 7.69 (s, 1H), 7.06 (dd, J=5.7, 2.7 Hz,1H), 4.27-4.24 (m, 2H), 4.13 (s, 2H), 3.72-3.69 (m, 2H), 3.32 (s, 3H),3.27 (s, 3H), 3.15 (t, J=7.2 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.05-1.94(m, 2H), 1.25 (s, 9H).

Example 1.247 Synthesis ofN-(5-fluoropyridin-3-yl)-2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 240)

Compound 240 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with4-(2-methoxyethoxy)-2-(trimethylstannyl)pyridine and replacingoxolan-3-amine with 5-fluoropyridin-3-amine. LCMS (ES) [M+1]⁺ m/z:429.2. ¹H NMR (300 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.35 (s, 1H), 8.71 (s,1H), 8.63 (t, J=1.7 Hz, 1H), 8.25 (d, J=2.6 Hz, 1H), 8.20-8.03 (m, 3H),7.81 (d, J=8.3 Hz, 1H), 7.82-7.64 (m, 2H), 4.51 (s, 2H), 3.43 (s, 3H),3.24 (t, J=7.3 Hz, 2H), 2.88 (t, J=7.8 Hz, 2H), 2.04 (p, J=7.6 Hz, 2H).

Example 1.248 Synthesis ofN-tert-butyl-2-({2-[4-(2-fluoroethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 241)

Compound 241 was synthesized similar to Compound 24 by replacing4-methyl-2-(trimethylstannyl)pyridine with4-(2-fluoroethoxy)-2-(trimethylstannyl)pyridine. LCMS (ES) [M+1]⁺ m/z:429.2. ¹H NMR (300 MHz, DMSO-d6) δ 8.50 (d, J=5.6 Hz, 1H), 7.89 (d,J=2.6 Hz, 1H), 7.69 (s, 1H), 7.08 (dd, J=5.6, 2.6 Hz, 1H), 4.91-4.82 (m,1H), 4.75-4.66 (m, 1H), 4.48-4.44 (m, 1H), 4.40-4.31 (m, 1H), 4.12 (s,2H), 3.27 (s, 3H), 3.15 (t, J=7.4 Hz, 2H), 2.81 (t, J=7.9 Hz, 2H),2.02-1.97 (m, 2H), 1.24 (s, 9H).

Example 1.249 Synthesis of2-({2-[4-(2-fluoroethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide(Compound 242)

Compound 242 was synthesized similar to Compound 135 by replacing4-methoxy-2-(trimethylstannyl)pyridine with4-(2-fluoroethoxy)-2-(trimethylstannyl)pyridine and replacingoxolan-3-amine with 5-amino-2-methoxypyridine. LCMS (ES) [M+1]⁺ m/z:453. ¹H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.46 (d, J=5.6 Hz, 1H),8.36 (d, J=2.6 Hz, 1H), 7.88 (dd, J=8.9, 2.7 Hz, 1H), 7.80 (d, J=2.6 Hz,1H), 7.04 (dd, J=5.6, 2.6 Hz, 1H), 6.77 (d, J=8.9 Hz, 1H), 4.84-4.75 (m,1H), 4.65-4.62 (m, 1H), 4.40 (s, 2H), 4.37-4.30 (m, 1H), 4.28-4.19 (m,1H), 3.80 (s, 3H), 3.38 (s, 3H), 3.22 (t, J=7.2 Hz, 2H), 2.84 (t, J=7.8Hz, 2H), 2.04-1.99 (m, 2H).

Example 1.250 Synthesis of2-({2-[4-(2-fluoroethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(1-methyl-1H-pyrazol-4-yl)acetamide(Compound 243)

Compound 243 was synthesized similar to Compound 135 by replacing4-methyl-2-(trimethylstannyl)pyridine with4-(2-fluoroethoxy)-2-(trimethylstannyl)pyridine and replacingoxolan-3-amine with 1-methylpyrazol-4-amine. LCMS (ES) [M+1]⁺ m/z: 426.¹H NMR (300 MHz, DMSO-d6) δ10.23 (s, 1H), 8.48 (d, J=5.6 Hz, 1H), 7.84(s, 1H), 7.78 (d, J=2.6 Hz, 1H), 7.40 (s, 1H), 7.05 (dd, J=5.6, 2.6 Hz,1H), 4.85-4.79 (m, 1H), 4.69-4.62 (m, 1H), 4.36-4.32 (m, 3H), 4.28-4.21(m, 1H), 3.76 (s, 3H), 3.35 (s, 3H), 3.20 (t, J=7.4 Hz, 2H), 2.83 (t,J=7.9 Hz, 2H), 2.05-1.95 (m, 2H).

Example 1.251 Synthesis ofN-(6-methoxypyridin-3-yl)-2-{methyl[2-(1,7-naphthyridin-6-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 244)

Step 1

Into a 1 L round-bottom flask were placed3-methylpyridine-2-carbonitrile (12.00 g, 101.58 mmol, 1.00 equiv), NBS(36.10 g, 203.16 mmol, 2.00 equiv), CCl₄ (500.00 mL) and AIBN (1.67 g,10.16 mmol, 0.10 equiv). The resulting solution was stirred for 5 h at80° C. The reaction solution was cooled to room temperature,concentrated to remove the solvent. The residue was purified by silicagel column with ethyl acetate/petroleum ether (1/2). This resulted in9.0 g (45%) of 3-(bromomethyl)pyridine-2-carbonitrile as yellow oil.LCMS (ES) [M+1]⁺ m/z: 197.

Step 2

Into a 250-mL round-bottom flask were placed3-(bromomethyl)pyridine-2-carbonitrile (9.00 g, 45.68 mmol, 1.00 equiv),CH₃CN (100.00 mL), TMSCN (13.59 g, 136.99 mmol, 3.00 equiv) and K₂CO₃(12.62 g, 91.31 mmol, 2.00 equiv). The resulting solution was stirredfor 12 h at 50° C. The reaction was cooled to room temperature, filteredand the filtrate was concentrated, the residue was purified by silicagel column with ethyl acetate/petroleum ether (2/3). This resulted in3.0 g (46%) of 3-(cyanomethyl)pyridine-2-carbonitrile as a yellow solid.LCMS (ES) [M+1]⁺ m/z: 144.

Step 3

Into a 100-mL 3-necked round-bottom flask were placed HBr (40% in H₂O)(20.00 mL), HOAc (20.00 mL), 3-(cyanomethyl)pyridine-2-carbonitrile(3.00 g, 20.96 mmol, 1.00 equiv). The resulting solution was stirred for1 h at room temperature. The solution was filtered, and the filtrate wasdiluted with of H₂O (20.00 mL), the pH value of the solution wasadjusted to 7 with NaHCO₃ solid, extracted with 3×50 mL of ethylacetate. The combined organic phase was dried over anhydrous sodiumsulfate, filtered and the filtrate was concentrated in vacuum. Thisresulted in 2.2 g (47%) of 8-bromo-1,7-naphthyridin-6-amine as yellowoil. LCMS (ES) [M+1]⁺ m/z: 224.

Step 4

Into a 250-mL round-bottom flask were placed8-bromo-1,7-naphthyridin-6-amine (2.20 g, 9.82 mmol, 1.00 equiv), EtOH(100.00 mL), KOH (663 mg, 11.82 mmol, 1.20 equiv), Pd/C (300 mg). Themixture was stirred for 2 h at room temperature under atmosphere ofhydrogen at pressure at 2-3 atm, filtered through the celite and thefiltrate was concentrated in vacuum. This resulted in 1.3 g (92%) of1,7-naphthyridin-6-amine as yellow oil. LCMS (ES) [M+1]⁺ m/z: 146.

Step 5

Into a 250-mL 3-necked round-bottom flask were placed1,7-naphthyridin-6-amine (1.30 g, 8.97 mmol, 1.00 equiv), HCl (c) (40.00mL). This was followed by the addition of NaNO₂ (1.36 g, 19.73 mmol,2.20 equiv) at 0° C. and stirred for 30 min. To this mixture was addedCuCl (897 mg, 8.97 mmol, 1.00 equiv), the resulting solution was stirredfor an additional 2 h at room temperature. The pH value of the solutionwas adjusted to 7 with NaOH (4 N) at 0° C., extracted with 3×50 mL ofethyl acetate. The combined organic phases were dried over anhydroussodium sulfate, filtered and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column with ethylacetate/petroleum ether (40%). This resulted in 530 mg (36%) of6-chloro-1,7-naphthyridine as yellow oil. LCMS (ES) [M+1]⁺ m/z: 165.

Step 6

Into a 40-mL vial purged and maintained with an inert atmosphere ofnitrogen were placed 6-chloro-1,7-naphthyridine (530 mg, 3.22 mmol, 1.00equiv), dioxane (10.00 mL), Sn₂Me₆ (1.16 g, 3.54 mmol, 1.10 equiv) andPd(dppf)Cl₂ (234 mg, 0.32 mmol, 0.10 equiv). The mixture was stirred for3 h at 100° C. The mixture was used to the next step directly withoutpurification. LCMS (ES) [M+1]⁺ m/z: 295.

Step 7

Into a 40-mL vial purged and maintained with an inert atmosphere ofnitrogen were placed 6-(trimethylstannyl)-1,7-naphthyridine (reactionsolution of last step), dioxane (5.00 mL), ethyl2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetate(350 mg, 1.30 mmol, 0.70 equiv) and Pd(dppf)Cl₂ (139 mg, 0.19 mmol, 0.10equiv). The mixture was stirred for 12 h at 100° C. The resultingmixture was cooled to room temperature, concentrated to remove thesolvent. The residue was purified by silica gel column with THF/PE(80%). This resulted in 507 mg (75%) of ethylN-(2-(1,7-naphthyridin-6-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinateas yellow oil. LCMS (ES) [M+1]⁺ m/z: 364.

Step 8

Into a 40-mL vial were placed ethyl2-[methyl[2-(1,7-naphthyridin-6-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetate(507 mg, 1.40 mmol, 1.00 equiv), EtOH (5.00 mL), LiOH·H₂O (117 mg, 2.79mmol, 2.00 equiv) and H₂O (10.00 mL). The resulting solution was stirredfor 1 h at room temperature. The reaction solution was concentrated andpurified by Prep-HPLC with the following conditions: Column, C 18-120 g,Mobile phase, Water and CH₃CN 5% increased to 10% within 9 min,Detector, 254 nm. The fraction was freezing dried, this resulted in 161mg (34%) of lithio2-[methyl[2-(1,7-naphthyridin-6-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetateas a white solid. LCMS (ES) [M−Li+1]⁺ m/z: 336.

Step 9

Into a 8-mL vial were placed lithio2-[methyl[2-(1,7-naphthyridin-6-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetate(161 mg, 0.47 mmol, 1.00 equiv), DMF (4.00 mL),5-amino-2-methoxypyridine (70 mg, 0.57 mmol, 1.20 equiv), DIEA (122 mg,0.95 mmol, 2.00 equiv) and HATU (215 mg, 0.57 mmol, 1.20 equiv). Theresulting solution was stirred for 2 h at room temperature. The reactionsolution was purified by Prep-HPLC with the following conditions:Column, Sunfire Prep C18 OBD Column, 50*250 mm 5 um, Mobile phase, Water(0.1% FA) and CH₃CN (5% Phase B up to 30% in 15 min), Detector, UV 254nm. This resulted in 89.6 mg (43.02%) ofN-(6-methoxypyridin-3-yl)-2-{methyl[2-(1,7-naphthyridin-6-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamideas an off-white solid. LCMS: (ES, m/z) [M+H]⁺: 442. ¹H NMR (300 MHz,DMSO-d6) δ 10.35 (s, 1H), 9.44 (s, 1H), 9.07 (dd, J=4.2, 1.5 Hz, 1H),8.82 (s, 1H), 8.39 (d, J=2.7 Hz, 1H), 8.33 (d, J=8.4 Hz, 1H), 8.15 (s,1H), 7.93 (dd, J=9.0, 2.7 Hz, 1H), 7.79 (dd, J=8.4, 4.2 Hz, 1H), 6.77(d, J=9.0 Hz, 1H), 4.48 (s, 2H), 3.79 (s, 3H), 3.42 (s, 3H), 3.24 (t,J=7.5 Hz, 2H), 2.88 (t, J=7.8 Hz, 2H), 2.09-1.98 (m, 2H).

Example 1.252 Synthesis of(2R)-3-methyl-N-(1-methyl-1H-pyrazol-4-yl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}butanamide(Compound 246)

Step 1

Into a 40-mL vial were placed2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (2.00 g, 10.58 mmol, 1.00equiv), methyl (2R)-2-amino-3-methylbutanoate (1.67 g, 12.73 mmol, 1.20equiv), NMP (20.00 mL) and DIEA (4.10 g, 31.74 mmol, 3.00 equiv). Theresulting solution was stirred for overnight at 80° C. The crude product(4 g) was purified by Prep-HPLC with the following conditions: Column,XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um; mobile phase, Water(0.1% HCOOH) and CAN (50% Phase B up to 90% in 11 min); Detector, 254nm. This resulted in 2.2 g (73.28%) of methyl(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)valinate as ayellow solid. LCMS (ES) [M+1]⁺ m/z: 284.

Step 2

Into a 100-mL 3-necked round-bottom flask were placed methyl(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)valinate (2.20 g,7.75 mmol, 1.00 equiv), DMF (30.00 mL). This was followed by theaddition of NaH (0.28 g, 11.67 mmol, 1.50 equiv) in portions at 0° C. Tothis was added methyl iodide (1.32 g, 9.30 mmol, 1.20 equiv) dropwisewith stirring at 0° C. The resulting solution was stirred for 2 h atroom temperature. The reaction was then quenched by the addition of 20mL of water/ice, extracted with 3×30 mL of ethyl acetate. The organiclayers were combined, dried over anhydrous sodium sulfate andconcentrated. The residue was applied onto a silica gel column withTHF/PE (6%). This resulted in 1.9 g (82.30%) of methylN-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylvalinateas yellow solid. LCMS (ES) [M+1]⁺ m/z: 298.

Step 3

Into a 100-mL round-bottom flask were placed methylN-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylvalinate(1.90 g, 6.38 mmol, 1.00 equiv), 2-(tributylstannyl)pyridine (3.05 g,8.28 mmol, 1.30 equiv), dioxane (30.00 mL) and Pd(dppf)Cl₂ (0.47 g, 0.64mmol, 0.10 equiv). The resulting solution was stirred for overnight at100° C. The resulting mixture was concentrated. The residue was appliedonto a silica gel column with THF/PE (70-100%). This resulted in 1.5 g(69.06%) of methylN-methyl-N-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)valinateas yellow oil. LCMS (ES) [M+1]+ m/z: 341.

Step 4

Into a 100-mL round-bottom flask were placed methylN-methyl-N-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)valinate(1.50 g, 4.41 mmol, 1.00 equiv), MeOH (10.00 mL), H₂O (10.00 mL). Thiswas followed by the addition of NaOH (0.35 g, 8.85 mmol, 2.00 equiv), inportions at 0° C. The resulting solution was stirred for overnight atroom temperature. The pH value of the solution was adjusted to 5-6 withcitric acid. The crude product (1 g) was purified by Prep-HPLC with thefollowing conditions: Column, XBridge Prep C18 OBD Column, 19 cm, 150mm, 5 um; mobile phase, Water (0.1% HCOOH) and CAN (10% Phase B up to40% in 11 min); Detector, 254 nm. This resulted in 800 mg (55.63%) of3-methyl-2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]butanoicacid as yellow solid. LCMS (ES) [M+1]⁺ m/z: 327.

Step 5

Into a 40-mL vial were placed3-methyl-2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]butanoicacid (330.00 mg, 1.01 mmol, 1.00 equiv), 5-amino-2-methoxypyridine(125.51 mg, 1.01 mmol, 1.00 equiv), DMF (5.00 mL) and DIEA (261.34 mg,2.02 mmol, 2.00 equiv). This was followed by the addition of T₃P (386.03mg, 1.21 mmol, 1.20 equiv) in portions at 0° C. The resulting solutionwas stirred for 3 h at room temperature. The crude product (1 g) waspurified by Prep-HPLC with the following conditions: Column, XBridgePrep C18 OBD Column, 19 cm, 150 mm, 5 um; mobile phase, Water (0.1%NH₃·H₂O) and CAN (50% Phase B up to 90% in 11 min); Detector, 254 nm.This resulted in 310 mg (70.89%) ofN-(6-methoxypyridin-3-yl)-3-methyl-2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]butanamideas white solid. LCMS (ES) [M+1]⁺ m/z: 433.

The crude product (310 mg) was purified by Prep-CHIRAL-HPLC with thefollowing conditions: Column, CHIRALPAK IC, 20*250 mm, 5 μm; mobilephase, n-Hexane/DCM=5/1 and IPA (15% in 25 min); Detector, 254 nM. Thisresulted in 83.7 mg (27.00%) of(2R)-3-methyl-N-(1-methyl-1H-pyrazol-4-yl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}butanamideas white solid. Chiral HPLC retention time: 3.83 min (condition: Column,YMC Cellulose-SB, 100*4.6 mm, 3 μm; mobile phase, n-Hexane/DCM=5/1 andisopropanol (10% in 6 min)). LCMS (ES, m/z): [M+H]⁺: 433. ¹H NMR (300MHz, DMSO-d6) δ 10.75 (s, 1H), 8.80-8.71 (m, 1H), 8.42 (d, J=7.9 Hz,1H), 8.31 (d, J=2.6 Hz, 1H), 8.04-7.87 (m, 2H), 7.60-7.50 (m, 1H), 6.76(d, J=8.9 Hz, 1H), 4.75 (d, J=11.1 Hz, 1H), 3.78 (s, 3H), 3.29-3.21 (m,1H), 3.18 (s, 3H), 3.15-3.01 (m, 1H), 3.01-2.74 (m, 2H), 2.49-2.39 (m,1H), 2.14-1.95 (m, 2H), 1.02 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H).

Example 1.253 Synthesis of(2S)—N-(6-methoxypyridin-3-yl)-3-methyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}butanamide(Compound 247)

The crude product from compound 246 step 1 (310 mg) was purified byPrep-CHIRAL-HPLC with the following conditions: Column, CHIRALPAK IC,30*250 mm, 5 μm; mobile phase, n-Hexane/DCM=5/1 and IPA (15% in 25 min);Detector, 254. This resulted in 105.5 mg (34.03%)(2S)—N-(6-methoxypyridin-3-yl)-3-methyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}butanamideas white solid. Chiral HPLC retention time: 5.19 min (condition: Column,YMC Cellulose-SB, 100*4.6 mm, 3 μm; mobile phase, n-Hexane/DCM=5/1 andisopropanol (10% in 6 min)). LCMS (ES, m/z): [M+H]⁺: 433. ¹H NMR (300MHz, DMSO-d6) δ 10.74 (s, 1H), 8.75 (dt, J=4.6, 1.5 Hz, 1H), 8.42 (dt,J=8.0, 1.2 Hz, 1H), 8.31 (d, J=2.6 Hz, 1H), 8.04-7.87 (m, 2H), 7.55(ddd, J=7.5, 4.8, 1.3 Hz, 1H), 6.76 (d, J=8.9 Hz, 1H), 4.75 (d, J=11.0Hz, 1H), 3.78 (s, 3H), 3.30-3.20 (m, 1H), 3.18 (s, 3H), 3.15-3.01 (m,1H), 3.01-2.74 (m, 2H), 2.51-2.37 (m, 1H), 2.17-1.91 (m, 2H), 1.02 (d,J=6.4 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H).

Example 1.254 Synthesis of(2R)-3-methyl-N-(1-methyl-1H-pyrazol-4-yl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}butanamide(Compound 248)

Compound 248 was synthesized similar to Compound 246 replacing5-amino-2-methoxypyridine with 1-methylpyrazol-4-amine. Chiral HPLCretention time: 3.68 min (condition: Column, YMC Cellulose-SB, 100*4.6mm, 3 μm; mobile phase, n-Hexane and ethanol (10% in 8 min)). LCMS (ES)[M+1]⁺ m/z: 406. ¹H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.85 (ddd,J=4.8, 1.7, 0.7 Hz, 1H), 8.41 (dt, J=7.9, 1.2 Hz, 1H), 7.99 (td, J=7.7,1.8 Hz, 1H), 7.88 (s, 1H), 7.57 (ddd, J=7.5, 4.8, 1.3 Hz, 1H), 7.34 (s,1H), 4.70 (d, J=11.1 Hz, 1H), 3.75 (s, 3H), 3.23 (dt, J=15.9, 8.0 Hz,1H), 3.16 (s, 3H), 3.14-3.00 (m, 1H), 3.00-2.74 (m, 2H), 2.49-2.35 (m,1H), 2.15-1.90 (m, 2H), 0.97 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H).

Example 1.255 Synthesis of(2R)-3-methyl-N-(1-methyl-1H-pyrazol-4-yl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}butanamide(Compound 249)

Compound 249 was synthesized similar to Compound 247 replacing5-amino-2-methoxypyridine with 1-methylpyrazol-4-amine. Chiral HPLCretention time: 4.82 min (condition: Column, YMC Cellulose-SB, 100*4.6mm, 3 μm; mobile phase, n-Hexane and ethanol (10% in 8 min)). LCMS (ES)[M+1]⁺ m/z: 406. ¹H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.85 (dt,J=5.1, 1.2 Hz, 1H), 8.41 (dt, J=7.9, 1.1 Hz, 1H), 7.99 (td, J=7.7, 1.7Hz, 1H), 7.88 (s, 1H), 7.57 (ddd, J=7.5, 4.7, 1.3 Hz, 1H), 7.35 (s, 1H),4.70 (d, J=11.0 Hz, 1H), 3.75 (s, 3H), 3.23 (dt, J=16.0, 8.1 Hz, 1H),3.16 (s, 3H), 3.14-3.00 (m, 1H), 3.00-2.74 (m, 2H), 2.49-2.35 (m, 1H),2.16-1.90 (m, 2H), 0.97 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H).

Example 1.256 Synthesis of(2R)-2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6-methoxypyridin-3-yl)propanamide(Compound 250)

Compound 250 was synthesized similar to Compound 108 replacingCyclohexanamine with 5-amino-2-methoxypyridine and replacing2-(tributylstannyl)pyridine with 3-(trimethylstannyl)isoquinoline. LCMS(ES) [M+1]⁺ m/z: 455. ¹H NMR (300 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.42(s, 1H), 8.85 (s, 1H), 8.38 (d, J=2.7 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H),8.17 (s, HCOOH), 8.03 (d, J=8.1 Hz, 1H), 7.94 (dd, J=8.7, 2.7 Hz, 1H),7.84-7.72 (m, 2H), 6.75 (d, J=8.7 Hz, 1H), 5.38 (q, J=6.9 Hz, 1H), 3.77(s, 3H), 3.29-3.13 (m, 2H), 3.25 (s, 3H), 2.95-2.86 (m, 2H), 2.08-1.98(m, 2H), 1.50 (d, J=6.9 Hz, 3H).

Example 1.257 Synthesis of(2R)—N-(3-fluorophenyl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)propanamide(Compound 251)

Step 1

Into a 50-mL 3-necked round-bottom flask were placed(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]propanoic acid (2.00 g, 9.84mmol, 1.00 equiv), DMF (20.00 mL), 3-fluoroaniline (1.20 g, 10.82 mmol,1.10 equiv) and DIEA (2.54 g, 19.68 mmol, 2.00 equiv). This was followedby the addition of HATU (4.12 g, 10.82 mmol, 1.10 equiv) in severalbatches at 0° C. After addition, the resulting solution was stirred for1 h at room temperature. The reaction was quenched with 20 mL of water,extracted with 3×20 mL of ethyl acetate. The combined organic phase waswashed with 3×20 ml of brine, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure, theresidue was purified by silica gel column with ethyl acetate/petroleumether (1:1). This resulted in 2.2 g (75%) of tert-butylN-[(1R)-1-[(3-fluorophenyl)carbamoyl]ethyl]-N-methylcarbamate as a whitesolid. LCMS (ES) [M+1]⁺ m/z: 297.

Step 2

Into a 50-mL round-bottom flask were placed tert-butylN-[(1R)-1-[(3-fluorophenyl)carbamoyl]ethyl]-N-methylcarbamate (2.20 g,7.42 mmol, 1.00 equiv) and DCM (10.00 mL). This was followed by theaddition of HCl (g) (2 M in EA) (19.00 mL, 37.10 mmol, 5.00 equiv)dropwise with stirring at 0° C. The resulting solution was stirred for 1h at room temperature. The mixture was concentrated in vacuum to removethe solvent. This resulted in 1.6 g (93%) of(2R)—N-(3-fluorophenyl)-2-(methylamino)propanamide hydrochloride as awhite solid. LCMS (ES) [M−HCl+1]⁺ m/z: 197.

Step 3

Into a 50-mL round-bottom flask were placed(2R)—N-(3-fluorophenyl)-2-(methylamino)propanamide hydrochloride (1.00g, 4.29 mmol, 1.00 equiv), NMP (20.00 mL),2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (1.06 g, 5.58 mmol, 1.30equiv) and DIEA (2.78 g, 21.49 mmol, 5.00 equiv). The resulting solutionwas stirred for 48 h at 60° C. in oil bath. The reaction mixture wascooled to room temperature, diluted with 20 mL of water and extractedwith 3×20 mL of ethyl acetate. The combined organic phases were washedwith 3×20 ml of brine, dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated under reduced pressure, the residue waspurified by silica gel column with ethyl acetate/petroleum ether (1:1).This resulted in 1.0 g (67%) of(2R)-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(3-fluorophenyl)propanamideas a white solid. LCMS (ES) [M+1]⁺ m/z: 349.

Step 4

Into a 100-mL three necked round bottom flask purged and maintained withan inert atmosphere of nitrogen were placed4-[2-(oxan-2-yloxy)ethoxy]-2-(trimethylstannyl)pyridine (Made in-situfrom 2-chloro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine withhexamethyldistannane) (1.60 g, 4.14 mmol, 1.00 equiv), toluene (60.00mL),(2R)-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(3-fluorophenyl)propanamide(1.01 g, 2.90 mmol, 0.70 equiv), Pd(PPh₃)₄ (479 mg, 0.41 mmol, 0.10equiv). The mixture was stirred for 12 h at 105° C. in oil bath. Thereaction mixture was cooled to room temperature, concentrated to removethe solvent, the residue was purified by silica gel column withdichloromethane/methanol (10:1). This resulted in 190 mg (9%) of(2R)—N-(3-fluorophenyl)-2-[methyl([2-[(2E)-3-[2-(oxan-2-yloxy)ethoxy]but-2-enimidoyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl])amino]propanamideas yellow oil. LCMS (ES) [M+1]⁺ m/z: 536.

Step 5

Into a 8-mL vial were placed(2R)—N-(3-fluorophenyl)-2-[methyl(2-[4-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]propanamide(190 mg, 0.35 mmol, 1.00 equiv), MeOH (4.00 mL) and TsOH (73 mg, 0.42mmol, 1.20 equiv). The resulting solution was stirred for 1 h at roomtemperature. The reaction solution was purified by Flash-Prep-HPLC withthe following conditions: Column, Welch XB-C18, 21.2*250 mm, 5 um,Mobile phase, Phase A: Water (0.05% NH₄OH) and Phase B: CH₃CN (10% PhaseB up to 65% in 15 min), Detector, UV 254 nm. The fraction was freezingdried, this resulted in 108.1 mg (68%) of(2R)—N-(3-fluorophenyl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)propanamideas a white solid. LCMS (ES, m/z): [M+H]⁺: 452. ¹H-NMR (300 MHz, DMSO-d₆,ppm): δ 10.58 (br, 1H), 8.49 (d, J=5.7 Hz, 1H), 7.88 (d, J=2.7 Hz, 1H),7.57-7.52 (m, 1H), 7.36-7.22 (m, 2H), 7.07 (dd, J=5.7, 2.7 Hz, 1H),6.86-6.80 (m, 1H), 5.28 (q, J=7.2 Hz, 1H), 4.92 (t, J=5.4 Hz, 1H), 4.13(t, J=4.2 Hz, 2H), 3.77-3.72 (m, 2H), 3.30-3.06 (m, 5H), 2.94-2.77 (m,2H), 2.06-1.95 (m, 2H), 1.46 (d, J=7.2 Hz, 3H).

Example 1.258 Synthesis ofN-(3-fluorophenyl)-2-[methyl(2-{4-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 252)

Step 1

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed a solution of1-(2-hydroxyethyl)pyrrolidine (4.82 g, 41.816 mmol, 1.1 equiv) in THF(50 mL). This was followed by the addition of NaH (60%) (1.83 g, 45.750mmol, 1.2 equiv), in portions at 0° C. in 15 min. The resulting solutionwas stirred for 1 hr at 0° C. To this was added2-chloro-4-fluoropyridine (5.00 g, 38.014 mmol, 1.00 equiv) dropwisewith stirring at 0° C. in 20 min. The resulting solution was stirredovernight at room temperature. The reaction was then quenched by theaddition of 50 mL of water/ice. The resulting solution was extractedwith 3×50 mL of ethyl acetate and the organic layers combined, washedwith 1×100 mL of brine. After filtration, the filtrate was dried overanhydrous sodium sulfate and concentrated. The residue was purified bysilica gel column eluted with ethyl acetate/petroleum ether (1/4). Thisresulted in 5.5 g (63.95%) of2-chloro-4-[2-(pyrrolidin-1-yl)ethoxy]pyridine as brown oil. LCMS (ES)[M+1]⁺ m/z: 227.

Step 2

Into a 40-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen were placed a solution of2-chloro-4-[2-(pyrrolidin-1-yl)ethoxy]pyridine (1.80 g, 7.940 mmol, 1.00equiv) in 1,4-Dioxane (20 mL), hexamethyldistannane (2.86 g, 8.734 mmol,1.1 equiv) and Pd(dppf)Cl₂ (400.00 mg, 0.547 mmol, 0.07 equiv). Theresulting solution was stirred overnight at 100° C. in an oil bath. Theresulting mixture was concentrated under vacuum. This resulted in 5.0 g(crude) of 4-[2-(pyrrolidin-1-yl)ethoxy]-2-(trimethylstannyl)pyridine asa solid. It was used directly in next step. LCMS (ES) [M+1]⁺ m/z: 357.

Step 3

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen were placed a solution of4-[2-(pyrrolidin-1-yl)ethoxy]-2-(trimethylstannyl)pyridine (5.00 gcrude, 14.082 mmol, 1.00 equiv) in toluene (50 mL), ethyl2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetate(2.28 g, 8.449 mmol, 0.6 equiv) and Pd(PPh₃)₄ (1.00 g, 0.865 mmol, 0.06equiv). The resulting solution was stirred overnight at 100° C. in anoil bath. The resulting mixture was concentrated. The residue waspurified by silica gel column eluted with dichloromethane/methanol(10/1). This resulted in 400 mg (crude) of ethyl2-[methyl(2-[4-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetateas brown oil. LCMS (ES) [M+1]⁺ m/z: 426.

Step 4

Into a 40-mL round-bottom flask were placed ethyl2-[methyl(2-[4-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetate(390.00 mg, 0.916 mmol, 1.00 equiv), MeOH/H₂O (3/1) (4 mL) and LiOH·H₂O(76.92 mg, 1.833 mmol, 2 equiv). The resulting solution was stirredovernight at room temperature. The resulting mixture was concentrated.This resulted in 350 mg (crude) of lithio2-[methyl(2-[4-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetateas a brown solid. LCMS (ES) [M−Li+H+1]⁺ m/z: 398.

Step 5

Into a 40-mL round-bottom flask were placed a solution of lithio2-[methyl(2-[4-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetate(320.00 mg, 0.805 mmol, 1.00 equiv) in DCM (4 mL), TEA (162.93 mg, 1.610mmol, 2 equiv), T3P (512.32 mg, 1.610 mmol, 2 equiv) and 3-fluoroaniline(107.35 mg, 0.966 mmol, 1.2 equiv). The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. The residue was purified by silica gel column withTHF/petroleum ether (10:1). The collected fractions were combined andconcentrated under vacuum. The residue was dissolved in 4 mL of MeOH andwas further purified by Prep-HPLC with the following conditions (WatersI): Column, Xbridge Prep C18 OBD column, 5 um, 19*150 mm; mobile phase,Water (0.1% TFA) and CH₃CN (30% CH₃CN up to 40% in 13 min); Detector, UV254 nm. This resulted in 35.0 mg (8.99%) ofN-(3-fluorophenyl)-2-[methyl(2-{4-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamideas a light yellow solid. LCMS (ES) [M+1]⁺ m/z: 491. ¹H NMR (300 MHz,Chloroform-d) δ 10.68 (s, 1H), 8.64 (s, 1H), 8.12 (s, 1H), 7.56 (d,J=11.4 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.24-7.14 (m, 1H), 7.14 (s, 1H),6.77-6.72 (m, 1H), 4.70 (s, 2H), 4.56 (s, 2H), 3.83 (s, 2H), 3.64 (s,3H), 3.58 (s, 2H), 3.42-3.26 (m, 2H), 3.11-3.06 (m, 4H), 2.23-2.16 (m,6H).

Example 1.259 Synthesis ofN-(6-methoxypyridin-3-yl)-2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide(Compound 253)

Step 1

Into a 40-mL vial purged and maintained with an inert atmosphere ofnitrogen were placed a mixture of4-(oxetan-3-yloxy)-2-(trimethylstannyl)pyridine (1.00 g, 3.185 mmol,1.00 equiv), toluene (20.0 mL), ethyl2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetate(859 mg, 0.003 mmol, 1.00 equiv), Pd(PPh₃)₄ (368 mg, 0.319 mmol, 0.10equiv). The resulting solution was stirred for 16 hours at 100° C. Theresulting mixture was concentrated. The residue was applied onto asilica gel column with dichloromethane/methanol (10/1). This resulted in540 mg (44.10%) of ethylN-methyl-N-(2-(4-(oxetan-3-yloxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycinateas brown oil. LCMS (ES) [M+1]⁺ m/z 385.

Step 2

Into a 20-mL vial were placed a mixture of ethylN-methyl-N-(2-(4-(oxetan-3-yloxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycinate(500 mg, 1.30 mmol, 1.00 equiv), MeOH (10.00 mL), H₂O (2.00 mL) and NaOH(104.04 mg, 2.602 mmol, 2.00 equiv). The resulting solution was stirredfor 2 hours at room temperature. The resulting mixture was concentratedand diluted with 20 mL of H₂O. The pH value of the solution was adjustedto 6 with HCl (2 mol/L). The resulting solids were collected byfiltration. This resulted in 420 mg (90.61%) ofN-methyl-N-(2-(4-(oxetan-3-yloxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycineas a white solid. LCMS (ES) [M+1]⁺ m/z 357.

Step 3

Into a 8-mL vial were placed a mixture ofN-methyl-N-(2-(4-(oxetan-3-yloxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycine(150 mg, 0.421 mmol, 1.00 equiv), DMA (5.00 mL),5-amino-2-methoxypyridine (104 mg, 0.842 mmol, 2.00 equiv), T3P (267 mg,0.842 mmol, 2.00 equiv) and Et₃N (127 mg, 1.26 mmol, 3.00 equiv). Theresulting solution was stirred for 2 hours at room temperature. Thecrude product was purified by Prep-HPLC with the following conditions:Column, Xbridge Prep C18 OBD Column, 19×150 mm, 5 um; mobile phase,phase A: H₂O (0.05% NH₃H₂O); phase B: CH₃CN/MeOH=1/1 (15% CH₃CN/MeOH upto 65% CH₃CN/MeOH in 15 min). This resulted in 52.7 mg (27.1%) ofN-(6-methoxypyridin-3-yl)-2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamideas an off-white solid. LCMS (ES) [M+1]⁺ m/z: 463. ¹H NMR (300 MHz,DMSO-d6) δ 8.46 (d, J=5.6 Hz, 1H), 8.37 (d, J=2.7 Hz, 1H), 7.91 (dd,J=8.9, 2.8 Hz, 1H), 7.64 (d, J=2.6 Hz, 1H), 6.85 (dd, J=5.6, 2.6 Hz,1H), 6.78 (d, J=8.8 Hz, 1H), 5.38-5.32 (m, 1H), 4.91 (t, J=6.7 Hz, 2H),4.53 (dd, J=7.4, 4.8 Hz, 2H), 4.39 (s, 2H), 3.80 (s, 3H), 3.37 (s, 3H)3.21 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.07-1.96 (m. 2H).

Example 1.260 Synthesis of2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]-N-(1-methyl-1H-pyrazol-4-yl)acetamide(Compound 254)

Compound 254 was synthesized similar to Compound 135 replacing of4-methoxy-2-(tributylstannyl)pyridine with4-(oxetan-3-yloxy)-2-(trimethylstannyl)pyridine and replacingoxolan-3-amine with 1-methyl-1H-pyrazol-4-amine. LCMS (ES) [M+1]⁺ m/z:436. ¹H NMR (300 MHz, DMSO-d6) δ 8.48 (d, J=5.5 Hz, 1H), 7.86 (s, 1H),7.58 (d, J=2.6 Hz, 1H), 7.42 (s, 1H), 6.88 (dd, J=5.9, 2.6 Hz, 1H),5.48-5.35 (m, 1H), 4.92 (t, J=6.7 Hz, 2H), 4.55 (dd, J=7.4, 4.8 Hz, 2H),4.35 (s, 2H), 3.76 (s, 3H), 3.41 (s, 3H), 3.19 (t, J=7.5 Hz, 2H), 2.83(t, J=7.8 Hz, 2H), 2.13-1.95 (m, 2H), 1.86 (s, 1H).

Example 1.261 Synthesis of2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-1-(piperidin-1-yl)ethan-1-one(Compound 255)

Compound 255 was synthesized similar to Compound 135 replacing of4-methoxy-2-(tributylstannyl)pyridine with3-(trimethylstannyl)isoquinoline and replacing oxolan-3-amine withpiperidine. LCMS (ES) [M+1]⁺ m/z: 402. ¹H NMR (300 MHz, DMSO-d6) δ 9.39(s, 1H), 8.71 (s, 1H), 8.23-8.15 (m, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.82(ddd, J=8.2, 6.9, 1.3 Hz, 1H), 7.73 (ddd, J=8.1, 6.9, 1.3 Hz, 1H), 4.59(s, 2H), 3.54-3.39 (m, 4H), 3.30 (s, 3H), 3.16 (t, J=7.2 Hz, 2H),2.92-2.80 (m, 2H), 2.05-1.95 (m, 2H), 1.72-1.59 (m, 4H), 1.48-1.38 (m,2H).

Example 1.262 Synthesis of2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-1-(4-methylpiperazin-1-yl)ethan-1-one(Compound 256)

Compound 256 was synthesized similar to Compound 135 replacing of4-methoxy-2-(tributylstannyl)pyridine with3-(trimethylstannyl)isoquinoline and replacing oxolan-3-amine with4-methylpiperazine. LCMS (ES) [M+1]⁺ m/z: 417. ¹H NMR (300 MHz, DMSO-d6)δ 9.40 (s, 1H), 8.71 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.1 Hz,1H), 7.82 (ddd, J=8.2, 6.9, 1.3 Hz, 1H), 7.73 (ddd, J=8.1, 6.9, 1.2 Hz,1H), 4.60 (s, 2H), 3.57 (s, 2H), 3.45 (s, 2H), 3.30 (s, 3H), 3.16 (t,J=7.3 Hz, 2H), 2.86 (t, J=8.1 Hz, 2H), 2.42 (s, 2H), 2.24 (s, 2H), 2.18(s, 3H), 2.02 (td, J=14.8, 14.1, 6.5 Hz, 2H).

Example 1.263 Synthesis ofN-(6-methoxypyridin-3-yl)-2-{methyl[2-(1,6-naphthyridin-7-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 257)

Step 1

To a stirred mixture of ethyl 2-(3-bromopyridin-2-yl)acetate (14 g, 57.3mmol, 1.0 equiv), Zn(CN)₂ (10.1 g, 86.03 mmol, 1.5 equiv) and K₂CO₃(15.8 g, 114.7 mmol, 2.0 equiv) in NMP (100 mL) was addedPd(dppf)Cl₂·CH₂Cl₂ (4.7 g, 5.73 mmol, 0.10 equiv) at 20° C. Theresulting mixture was heated to 70° C. and stirred at this temperaturefor 16 h under N₂ atmosphere. The resulting mixture was cooled to 25° C.and quenched with water, extracted with EtOAc (100 mL×3), organic layerwas combined, concentrated, the residue was purified by silica gelcolumn chromatography to give ethyl 2-(3-cyanopyridin-2-yl)acetate (9.0g, 81.8% yield) as a yellow gum. LCMS (ES) [M+1]⁺ m/z: 191.

Step 2

To a stirred mixture of ethyl 2-(3-cyanopyridin-2-yl)acetate (6.0 g,31.5 mmol, 1.0 equiv) in AcOH (12 mL) and EtOH (60 mL) was added Pd/C(600 mg) at 20° C. The resulting mixture was heated to 40° C. andstirred at that temperature for 16 h under H₂ atmosphere (10 atm). Theresulting mixture was cooled to 25° C., filtered and concentrated. Theresidue was purified by silica gel column chromatography to give6,8-dihydro-5H-1,6-naphthyridin-7-one (4.0 g, 85.6%) as a yellow solid.LCMS (ES) [M+1]⁺ m/z: 149.

Step 3

To a stirred solution of 6,8-dihydro-5H-1,6-naphthyridin-7-one (1.5 g)in phenylphosphonic dichloride (10 mL) was heated to 130° C. and stirredat this temperature for 16 h. The resulting mixture was cooled to 25°C., poured into 50 mL of water and adjusted pH to 8 with solid NaHCO₃.The mixture was extracted with EtOAc, organic layer was separated andconcentrated. The residue was purified by silica gel columnchromatography to give 7-chloro-1,6-naphthyridine (400 mg, 25.5% yield)as a yellow solid. LCMS (ES) [M+1]⁺ m/z: 165.

Step 4

To a stirred solution of 7-chloro-1,6-naphthyridine (200 mg, 1.21 mmol,1.0 equiv) in Toluene (5 mL) was added Sn₂Me₆ (438 mg, 1.33 mmol, 1.1equiv) and Pd(dppf)Cl₂·CH₂Cl₂ (89 mg, 0.12 mmol, 0.1 equiv) at roomtemperature. The reaction was stirred at 100° C. for 3 h under N₂atmosphere. The reaction mixture was used for next step without furtherpurification (7-(trimethylstannyl)-1,6-naphthyridine: theoretical weight358 mg). LCMS (ES) [M+1]⁺ m/z: 295.

Step 5

To a mixture of 7-(trimethylstannyl)-1,6-naphthyridine (358 mg, 1.21mmol, 1.0 equiv) in toluene (10 mL) were added2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide(296 mg, 0.85 mmol, 0.70 equiv) and Pd(PPh₃)₄ (140 mg, 0.12 mmol, 0.1equiv) at room temperature. The reaction was purged and maintained withan inert atmosphere of argon for 2 min. The resulting solution wasstirred for 16 hr at 100° C., cooled and concentrated under vacuum. Theresidue was applied onto a silica gel column with THF/petroleum ether(1:50 to 10:1) to give 150 mg crude product, which was further purifiedby preparatory HPLC (Column, C18; Flow rate: 20 mL/min Column: DAICELCHIRALPAK IC, 250*20 mm, 220 nm) to giveN-(6-methoxypyridin-3-yl)-2-[methyl[2-(1,6-naphthyridin-7-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide(55 mg, 10.24%) as an off white solid. LCMS (ES) [M+1]⁺ m/z: 442. ¹H NMR(300 MHz, DMSO-d₆) δ 10.31 (s, 1H), 9.46 (s, 1H), 9.16 (d, J=4.2 Hz,1H), 8.82 (s, 1H), 8.62 (d, J=8.3 Hz, 1H), 8.38 (d, J=2.7 Hz, 1H), 7.92(dd, J=8.6, 2.7 Hz, 1H), 7.72 (dd, J=8.3, 4.2 Hz, 1H), 6.75 (d, J=8.9Hz, 1H), 4.49 (s, 2H), 3.78 (s, 3H), 3.40 (s, 3H), 3.23 (t, J=7.4 Hz,2H), 2.88 (t, J=7.8 Hz, 2H), 2.09-2.02 (m, 2H).

Example 1.264 Synthesis ofN-(6-methoxypyridin-3-yl)-2-{methyl[2-(2,6-naphthyridin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 258)

Step 1

Into a 500 mL 3-necked round-bottom flask were placed ethyl2-(pyridin-3-yl)acetate (20.00 g, 121.07 mmol, 1.00 equiv) and CHCl₃(300.00 mL). This was followed by the addition of mCPBA (31.34 g, 181.61mmol, 1.50 equiv) in portions at 0° C. The resulting solution wasstirred for 5 h at room temperature. The reaction was then quenched bythe addition of Sat. Na₂SO₃. The pH value of the solution was adjustedto 8-9 with Sat. Na₂CO₃. The resulting solution was extracted with 3×300mL of dichloromethane and the organic layers were combined, dried overanhydrous sodium sulfate and concentrated. The residue was applied ontoa silica gel column with dichloromethane/methanol (100/5). This resultedin 20 g (91.17%) of 3-(2-ethoxy-2-oxoethyl)pyridin-1-ium-1-olate asoff-white solid. LCMS (ES) [M+1]⁺ m/z: 182.

Step 2

Into a 500 mL round-bottom flask, was placed3-(2-ethoxy-2-oxoethyl)pyridin-1-ium-1-olate (20.00 g, 110.38 mmol, 1.00equiv), ethyl iodide (51.65 g, 331.16 mmol, 3.00 equiv). The resultingsolution was stirred for 6 h at 45° C. The resulting solution was addedCH₃CN (350.00 mL), K₂CO₃ (45.77 g, 331.14 mmol, 3.00 equiv), TMSCN(32.85 g, 331.14 mmol, 3.00 equiv). The resulting solution was stirredfor overnight at 50° C. The reaction mixture was cooled to roomtemperature. The solids were filtered out and the filtrate wasconcentrated. The residue was applied onto a silica gel column withTHF/PE (10%). This resulted in 10 g (47.63%) of ethyl2-(4-cyanopyridin-3-yl)acetate as yellow oil. LCMS (ES) [M+1]⁺ m/z: 191.

Step 3

Into a 250 mL pressure tank reactor were placed ethyl2-(4-cyanopyridin-3-yl)acetate (10.00 g, 52.57 mmol, 1.00 equiv), EtOH(80.00 mL), AcOH (20.00 mL) and Pd/C (0.56 g, 5.26 mmol, 0.10 equiv).The resulting solution was stirred for 6 h at 35° C. The solids werefiltered out and the filtrate was concentrated. The crude product (10 g)was purified by Prep-HPLC with the following conditions: Column, XBridgePrep C18 OBD Column, 19 cm, 150 mm, 5 um; mobile phase, Water (0.1%NH₃·H₂O) and CAN (10% Phase B up to 30% in 11 min); Detector, 254 nM.This resulted in 6 g (77%) of 2,4-dihydro-1H-2,6-naphthyridin-3-one asyellow solid. LCMS (ES) [M+1]+ m/z: 149.

Step 4

Into a 250 mL round-bottom flask were placed2,4-dihydro-1H-2,6-naphthyridin-3-one (6.00 g, 40.49 mmol, 1.00 equiv)and phenylphosphonic dichloride (60.00 mL). The resulting solution wasstirred for 3 h at 125° C. The reaction mixture was cooled to roomtemperature. The pH value of the solution was adjusted to 8 with Sat.NaHCO₃. The resulting solution was extracted with 3×300 mL ofdichloromethane and the organic layers combined, dried over anhydroussodium sulfate and concentrated. The residue was applied onto a silicagel column with THF/PE (30%). This resulted in 350 mg (5.25%) of3-chloro-2,6-naphthyridine as yellow solid. LCMS (ES) [M+1]⁺ m/z: 165.

Step 5

Into a 40-mL vial were placed 3-chloro-2,6-naphthyridine (350.00 mg,2.13 mmol, 1.00 equiv), hexamethyldistannane (905.72 mg, 2.76 mmol, 1.30equiv), toluene (10.00 mL) and Pd(dppf)Cl₂ (155.60 mg, 0.21 mmol, 0.10equiv). The resulting solution was stirred for 3 h at 100° C. Thereaction mixture was cooled to room temperature and added ethyl2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetate(401.51 mg, 1.49 mmol, 0.70 equiv). The resulting solution was thenstirred for overnight at 100° C. The reaction mixture was cooled to roomtemperature and concentrated. The residue was applied onto a silica gelcolumn with THF/PE (50%). This resulted in 300 mg (38.82%) of ethyl2-[methyl[2-(2,6-naphthyridin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetateas yellow solid. LCMS (ES) [M+1]⁺ m/z: 364.

Step 6

Into a 100-mL round-bottom flask were placed ethyl2-[methyl[2-(2,6-naphthyridin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetate(300.00 mg, 0.83 mmol, 1.00 equiv), MeOH (5.00 mL) and H₂O (5.00 mL).This was followed by the addition of LiOH·H₂O (69.28 mg, 1.65 mmol, 2.00equiv) in portions at 0° C. The resulting solution was stirred for 3 hat room temperature and the pH value of the solution was adjusted to 7with citric acid. The crude product (0.5 g) was purified by Prep-HPLCwith the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150 mm, 5 um; mobile phase, Water and AcCN (10% Phase B up to 30% in11 min); Detector, 254 nm. This resulted in 160 mg (57.79%) of[methyl[2-(2,6-naphthyridin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]aceticacid as yellow solid. LCMS (ES) [M+1]⁺ m/z: 336.

Step 7

Into a 40 mL vial was placed[methyl[2-(2,6-naphthyridin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]aceticacid (160.00 mg, 0.47 mmol, 1.00 equiv), DMF (5.00 mL), DIEA (123.32 mg,0.95 mmol, 2 equiv) and 5-amino-2-methoxypyridine (59.23 mg, 0.47 mmol,1.00 equiv). This was followed by the addition of HATU (217.68 mg, 0.57mmol, 1.20 equiv) in portions at 0° C. The resulting solution wasstirred for 2 h at room temperature. The crude product (1 g) waspurified by Prep-HPLC with the following conditions: Column, XBridgePrep C18 OBD Column, 19 cm, 150 mm, 5 um; mobile phase, Water (0.1%NH₃·H₂O) and AcCN/MeOH=1:1 (30% Phase B up to 70% in 11 min); Detector,254 nm. This resulted in 127 mg (33.97%) ofN-(6-methoxypyridin-3-yl)-2-[methyl[2-(2,6-naphthyridin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide;tris(trifluoroacetic acid) as orange solid. LCMS (ES, m/z): [M+H]⁺: 442.¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 10.61 (s, 1H), 9.70 (s, 1H), 9.43 (s,1H), 9.14 (s, 1H), 8.91 (d, J=5.6 Hz, 1H), 8.44 (d, J=2.7 Hz, 1H), 8.22(d, J=5.7 Hz, 1H), 7.96 (dd, J=8.9, 2.8 Hz, 1H), 6.79 (d, J=8.9 Hz, 1H),4.75 (s, 2H), 3.78 (s, 3H), 3.63 (s, 3H), 3.36-3.30 (m, 2H), 3.11 (t,J=7.8 Hz, 2H), 2.19-2.02 (m, 2H).

Example 1.265 Synthesis of2-{[2-(4-ethoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(2-methoxypyrimidin-5-yl)acetamide(Compound 259)

Compound 259 was synthesized similar to Compound 135 by replacing of4-methoxy-2-(tributylstannyl)pyridine with4-ethoxy-2-(tributylstannyl)pyridine and replacing oxolan-3-amine with2-methoxypyrimidin-5-amine. LCMS (ES) [M+1]⁺ m/z: 436. ¹H NMR (300 MHz,DMSO-d6) δ 10.49 (s, 1H), 8.76 (s, 2H), 8.42 (d, J=5.5 Hz, 1H), 7.72 (d,J=2.5 Hz, 1H), 6.98 (dd, J=5.7, 2.5 Hz, 1H), 4.39 (s, 2H), 4.05 (q,J=6.9 Hz, 2H), 3.87 (s, 3H), 3.38 (s, 3H), 3.21 (t, J=7.4 Hz, 2H), 2.83(t, J=7.8 Hz, 2H), 2.07-1.96 (m, 2H), 1.29 (t, J=7.0 Hz, 3H).

Example 1.266 Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(2-methoxypyrimidin-5-yl)acetamide(Compound 260)

Compound 260 was synthesized similar to Compound 210 by replacing5-amino-2-methoxypyridine with 2-methoxypyrimidin-5-amine. LCMS (ES)[M+1]⁺ m/z: 480. ¹H NMR (300 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.74 (s,2H), 8.43 (d, J=5.6 Hz, 1H), 7.77 (d, J=2.5 Hz, 1H), 7.03 (dd, J=5.7,2.6 Hz, 1H), 4.66 (s, 1H), 4.42 (s, 2H), 3.87 (s, 3H), 3.80 (s, 2H),3.38 (s, 3H), 3.22 (t, J=7.3 Hz, 2H), 2.84 (t, J=7.8 Hz, 2H), 2.08-1.99(m, 2H), 1.16 (s, 6H).

Example 1.267 Synthesis ofN-tert-butyl-2-{[2-(6-methoxyisoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 261)

Compound 261 was synthesized similar to Compound 24 by replacing4-methyl-2-(tributylstannyl)pyridine with6-methoxy-3-(trimethylstannyl)isoquinoline. LCMS (ES) [M+1]⁺ m/z 420. ¹HNMR (300 MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.80 (s, 1H), 8.16 (HCOOH), 8.08(d, J=9.0 Hz, 1H), 7.81 (s, 1H), 7.50 (s, 1H), 7.33 (dd, J=8.9, 2.5 Hz,1H), 4.19 (s, 2H), 3.94 (s, 3H), 3.33 (s, 3H), 3.17 (t, J=7.5 Hz, 2H),2.85 (t, J=7.9 Hz, 2H), 2.04-1.99 (m, 2H), 1.23 (s, 9H).

Example 1.268 Synthesis ofN-tert-butyl-2-{[2-(7-methoxyisoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 262)

Compound 262 was synthesized similar to Compound 24 by replacing4-methyl-2-(tributylstannyl)pyridine with7-methoxy-3-(trimethylstannyl)isoquinoline. LCMS (ES) [M+1]⁺ m/z 420. ¹HNMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 8.79 (s, 1H), 8.17 (HCOOH), 8.03(d, J=9.0 Hz, 1H), 7.79 (s, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.48 (dd,J=9.0, 2.5 Hz, 1H), 4.19 (s, 2H), 3.95 (s, 3H), 3.32 (s, 3H), 3.17 (t,J=7.3 Hz, 2H), 2.84 (t, J=7.8 Hz, 2H), 2.06-1.99 (m, 2H), 1.23 (s, 9H).

Example 1.269 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-1-(piperidin-1-yl)ethan-1-one(Compound 263)

Compound 263 was synthesized similar to Compound 144 by replacingcyclohexylamine with piperidine. LCMS (ES) [M+1]⁺ m/z 412. ¹H NMR (300MHz, DMSO-d₆) δ 8.45 (d, J=5.7 Hz, 1H), 7.75 (d, J=2.7 Hz, 1H), 7.03(dd, J=5.7, 2.7 Hz, 1H), 4.92 (t, J=5.4 Hz, 1H), 4.51 (s, 2H), 4.13 (t,J=4.8 Hz, 2H), 3.75 (q, J=5.1 Hz, 2H), 3.47-3.37 (m, 4H), 3.25 (s, 3H),3.13 (t, J=7.5 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.04-1.93 (m, 2H), 1.61(s, 4H), 1.44 (s, 2H).

Example 1.270 Synthesis ofN-(6-fluoropyridin-3-yl)-2-[methyl({2-[1-(oxan-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide(Compound 264)

Compound 264 was synthesized similar to Compound 135 by replacing4-methoxy-2-(tributylstannyl)pyridine with1-(oxan-2-yl)-5-(tributylstannyl)-1H-pyrazolo[3,4-c]pyridine andreplacing oxolan-3-amine with 6-fluoro-3-pyridinylamine. LCMS (ES)[M+1]⁺ m/z: 503.2. ¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.10-8.94(m, 1H), 8.52 (d, J=2.3 Hz, 1H), 8.37 (s, 1H), 8.22 (ddd, J=8.8, 7.3,2.8 Hz, 1H), 7.17 (dd, J=8.8, 3.2 Hz, 1H), 6.18 (dd, J=9.2, 2.5 Hz, 1H),4.73 (s, 2H), 3.92-3.76 (m, 2H), 3.58 (s, 3H), 3.25 (m, 2H), 3.08 (t,J=7.9 Hz, 2H), 2.45-2.30 (m, 1H), 2.16-2.01 (m, 4H), 1.82-1.70 (m, 1H),1.66-1.57 (m, 2H).

Example 1.271 Synthesis ofN-(5-methoxypyridin-2-yl)-2-[methyl(2-{1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 265)

Compound 265 was synthesized similar to Compound 266 by replacing6-fluoropyridine-3-amine with 5-methoxypyridin-2-amine. LCMS (ES+):[M+H]⁺=431.1. ¹H NMR (400 MHz, DMSO-d6) δ 13.88 (s, 1H), 10.77 (s, 1H),9.11 (s, 1H), 8.78 (d, J=1.3 Hz, 1H), 8.16-8.09 (m, 2H), 7.96 (d, J=9.0Hz, 1H), 7.39 (dd, J=9.1, 3.1 Hz, 1H), 4.58 (s, 2H), 3.78 (s, 3H),3.30-3.18 (m, 9H), 2.92 (t, J=7.8 Hz, 2H), 2.05 (p, J=7.9 Hz, 2H).

Example 1.272 Synthesis ofN-(5-methoxypyridin-2-yl)-2-[methyl(2-{1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 266)

N-(6-Fluoropyridin-3-yl)-2-[methyl({2-[1-(oxan-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide(53 mg; 0.11 mmol; 1 eq.) was dissolved in methanol (1 ml) and cooled inan ice water bath. Hydrogen chloride solution (1 mL; 6 mol/Lisopropanol) was added slowly and the reaction was stirred at 25° C.After 3 h, more HCl (0.2 ml) was added and the reaction stirred for anadditional 1.5 h. The reaction solvent was evaporated and the residuewas purified by reverse phase chromatography (Waters XSelect CSH C18column, 0-60% acetonitrile/0.1% aqueous formic acid gradient) to giveN-(6-fluoropyridin-3-yl)-2-[methyl(2-{1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(22 mg, 49%) as a white solid. LCMS (ES+): [M+H]⁺=419.0. ¹H NMR (400MHz, dmso) δ 13.83 (s, 1H), 10.73 (s, 1H), 9.08 (s, 1H), 8.78-8.73 (m,1H), 8.48 (d, J=2.8 Hz, 1H), 8.21 (ddd, J=8.8, 7.3, 2.8 Hz, 1H), 8.16(s, 1H), 7.16 (dd, J=8.9, 3.2 Hz, 1H), 4.52 (s, 2H), 3.45 (s, 3H),3.27-3.19 (m, 2H), 2.95-2.86 (m, 2H), 2.11-1.98 (m, 2H).

Example 1.273 Synthesis of2-[methyl(2-{1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]-N-(6-methylpyridin-3-yl)acetamide(Compound 267)

Compound 267 was synthesized similar to Compound 266 by replacing6-fluoropyridine-3-amine with 6-methylpyridin-3-amine. LCMS (ES+):[M+H]⁺=415.1. ¹H NMR (400 MHz, dmso) δ 11.81 (s, 1H), 9.22 (s, 1H), 9.09(s, 1H), 9.02 (s, 1H), 8.50-8.31 (m, 2H), 7.69-7.63 (m, 1H), 4.83 (s,2H), 3.61 (s, 3H), 3.09 (t, J=7.9 Hz, 2H), 2.55 (s, 3H), 2.17-2.09 (m,2H).

Example 1.274 Synthesis ofN-(6-methoxypyridin-3-yl)-2-{methyl[2-(2,7-naphthyridin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 268)

Step 1

To a solution of 4-methylpyridine-3-carbonitrile (10 g, 84.646 mmol,1.00 equiv) in THE (100 mL) was added dropwise LiHDMS (1.0 M in THF, 170mL, 169.292 mmol, 2 equiv)) at −78° C. under N₂ atmosphere. The reactionmixture was stirred at −78° C. for 1 h. A solution of dimethyl carbonate(9.50 g, 105.464 mmol, 1.25 equiv) in 50 mL THE was added dropwise andthe mixture was stirred for another 1 h at −78° C. The resulting mixturewas stirred for 2 h at −78° C. to 0° C. under nitrogen atmosphere. Thereaction was quenched with NH₄Cl (200 mL) and the resulting mixture wasextracted with EtOAc (2×200 mL). The combined organic layers were washedwith water (1×100 mL), dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography, eluted with PE/EtOAc(10:1) to yield methyl 2-(3-cyanopyridin-4-yl)acetate (10.1 g, 67.73%)as a yellow oil. LCMS (ES) [M+1]⁺ m/z: 177;

Step 2

To a solution of methyl 2-(3-cyanopyridin-4-yl)acetate (10.00 g, 56.762mmol, 1.00 equiv) in EtOH (200.00 mL) and AcOH (20.00 mL) was added Pd/C(1.21 g, 11.352 mmol, 0.20 equiv) under nitrogen atmosphere in a 500 mL3-necked round-bottom flask. The mixture was charged with H₂ (1 atm) at40° C. for overnight. The resulting mixture was filtered; the filtercake was washed with MeOH (3×100 mL). The filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford2,4-dihydro-1H-2,7-naphthyridin-3-one (4 g, 47.56%) as a yellow oil.LCMS (ES) [M+1]⁺ m/z: 149;

Step 3

A solution of 2,4-dihydro-1H-2,7-naphthyridin-3-one (1.00 g, 6.749 mmol,1.00 equiv) and DDQ (1.69 g, 7.424 mmol, 1.10 equiv) in Toluene (30.00mL) was stirred for 1 h at room temperature under air atmosphere. To theabove mixture was added POCl₃ (10.00 mL, 65.236 mmol, 15.90 equiv). Theresulting mixture was stirred for additional 16 h at 90° C. Theresulting mixture was concentrated under reduced pressure. The reactionwas quenched with water at room temperature. The mixture was adjusted topH 8 with saturated NaHCO₃ (aq.). The resulting mixture was extractedwith EtOAc (2×200 mL). The combined organic layers were washed withbrine (1×100 mL), dried over anhydrous Na₂SO₄ and filtered. the filtratewas concentrated under reduced pressure and the residue was purified bysilica gel column chromatography, eluted with PE/EtOAc (1:1) to afford3-chloro-2,7-naphthyridine (50 mg, 4.50%) as a yellow solid. LCMS (ES)[M+1]⁺ m/z: 165.

Step 4

To a solution of 3-chloro-2,7-naphthyridine (220.00 mg, 1.337 mmol, 1.00equiv) and hexamethyldistannane (481.72 mg, 1.471 mmol, 1.10 equiv) intoluene (5.00 mL, 46.995 mmol) were added Pd(dppf)Cl2 CH2Cl2 (108.89 mg,0.134 mmol, 0.10 equiv). After stirring for 2 h at 100° C. under anitrogen atmosphere, the mixture was allowed to cool down to roomtemperature. The mixture was then added2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide(325.42 mg, 0.936 mmol, 0.70 equiv) and Pd(PPh₃)₄ (108.89 mg, 0.134mmol, 0.10 equiv). The resulting mixture was stirred for additional 16 hat 100° C. After cooling the resulting mixture was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography, eluted with PE/THF (1:10) to provideN-(6-methoxypyridin-3-yl)-2-[methyl[2-(2,7-naphthyridin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide(30 mg, 7.3%) as a white solid. LCMS (ES) [M+1]+ m/z: 442; 1H NMR (300MHz, DMSO-d6) δ 10.35 (s, 1H), 9.58 (d, J=5.2 Hz, 2H), 8.87-8.62 (m,2H), 8.39 (d, J=2.7 Hz, 1H), 7.93 (dd, J=8.9, 2.7 Hz, 1H), 7.74 (d,J=5.8 Hz, 1H), 6.77 (d, J=8.9 Hz, 1H), 4.47 (s, 2H), 3.79 (s, 3H), 3.42(s, 3H), 3.31-3.11 (m, 2H), 2.89 (t, J=7.8 Hz, 2H), 2.07-2.02 (m, 2H).

Example 1.275 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(4-methoxyphenyl)acetamide(Compound 269)

Compound 269 was synthesized similar to Compound 144 by replacingcyclohexylamine with 4-methoxyaniline. LCMS (ES) [M+1]⁺ m/z 450. ¹H NMR(300 MHz, DMSO-d₆) δ 10.07 (s, 1H), 8.44 (d, J=5.6 Hz, 1H), 7.80 (d,J=2.6 Hz, 1H), 7.55-7.43 (m, 2H), 7.00 (dd, J=5.6, 2.6 Hz, 1H),6.92-6.79 (m, 2H), 4.90 (t, J=5.4 Hz, 1H), 4.39 (s, 2H), 4.03 (t, J=4.7Hz, 2H), 3.71 (s, 3H), 3.77-3.62 (m, 2H), 3.35 (s, 3H), 3.20 (t, J=7.3Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.01 (p, J=7.8 Hz, 2H).

Example 1.276 Synthesis of2-({2-[5-(hydroxymethyl)isoquinolin-3-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methylpyridin-3-yl)acetamide(Compound 270)

Step 1

Into a 1000-mL round-bottom flask was placed 1,3-dichloroisoquinoline(30.00 g, 151.477 mmol, 1.00 equiv), NBS (28.31 g, 159.051 mmol, 1.05equiv), AcCN (600.00 mL) and H₂SO₄ (30.00 mL). The resulting solutionwas stirred for 90 h at room temperature. The solids were collected byfiltration. This resulted in 18 g (42.91%) of5-bromo-1,3-dichloroisoquinoline as a yellow solid. LCMS (ES) [M+1]⁺ m/z276.

Step 2

Into a 500-mL round-bottom flask was placed5-bromo-1,3-dichloroisoquinoline (15.00 g, 54.163 mmol, 1.00 equiv),AcOH (150.00 mL), HCl (30.00 mL) and Sn (19.34 g, 162.490 mmol, 3equiv). The resulting solution was stirred for 0.5 hr at 60° C. Theresulting solution was extracted with 3×200 mL of ethyl acetate, organiclayers were combined, washed with 3×200 ml of brine and filtered. Thefiltrate was concentrated and the residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:5). This resulted in 5.5 g(41.87%) of 5-bromo-3-chloroisoquinoline as a light yellow solid. LCMS(ES) [M+1]⁺ m/z 242.

Step 3

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed 5-bromo-3-chloroisoquinoline(3.00 g, 12.371 mmol, 1.00 equiv), THE (30.00 mL). This was followed bythe addition of n-BuLi in hexanes (5.9 mL, 14.862 mmol, 1.20 equiv)dropwise with stirring at −78° C. The resulting solution was stirred for0.5 hr at −78° C. To this was added DMF (2.71 g, 37.113 mmol, 3.00equiv) dropwise with stirring at −78° C. The resulting solution waswarmed up to room temperature and stirred for an additional 2 hr. Thereaction was then quenched by the addition of 100 mL of NH₄Cl. Theresulting solution was extracted with 2×50 mL of ethyl acetate. Organiclayers were combined, washed with brine and dried over anhydrous sodiumsulfate. The mixture was filtered, and the filtrate was concentrated.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:1). This resulted in 730 mg (30.7%) of3-chloroisoquinoline-5-carbaldehyde as a light yellow solid. LCMS (ES)[M+1]⁺ m/z 192.

Step 4

Into a 40-mL round-bottom flask was placed3-chloroisoquinoline-5-carbaldehyde (730.00 mg, 3.810 mmol, 1.00 equiv),THE (10.00 mL) and NaBH₄ (432.41 mg, 11.429 mmol, 3 equiv). Theresulting solution was stirred for 2 hr at room temperature. Thereaction was then quenched by the addition of 10 mL of water andextracted with 3×20 mL of ethyl acetate. The combined organic layerswere washed with 3×20 mL of brine, dried over anhydrous sodium sulfateand concentrated. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:1). This resulted in 730 mg (98.9%) of(3-chloroisoquinolin-5-yl)methanol as a light yellow solid. LCMS (ES)[M+1]⁺ m/z 194.

Step 5

Into a 40-mL round-bottom flask were placed(3-chloroisoquinolin-5-yl)methanol (730.00 mg, 3.770 mmol, 1.00 equiv),DCM (10 mL), TBSCl (852.35 mg, 5.655 mmol, 1.50 equiv), imidazole(513.31 mg, 7.540 mmol, 2 equiv). The resulting solution was stirred for12 hr at room temperature. The resulting mixture was concentrated. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:10). This resulted in 800 mg (68.9%) of5-[[(tert-butyldimethylsilyl)oxy]methyl]-3-chloroisoquinoline as yellowoil. LCMS (ES) [M+1]⁺ m/z 308.

Step 6

Into a 40-mL round-bottom flask were placed2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(6-methylpyridin-3-yl)acetamide(215.53 mg, 0.650 mmol, 1.00 equiv), hexamethyldistannane (212.82 mg,0.650 mmol, 1 equiv), Dioxane (6 mL) and Pd(dppf)Cl₂·CH₂Cl₂ (52.92 mg,0.065 mmol, 0.10 equiv). The resulting solution was stirred for 3 h at100° C. and was cooled and added5-[[(tert-butyldimethylsilyl)oxy]methyl]-3-chloroisoquinoline (200.00mg, 0.650 mmol, 1.00 equiv) and Pd(dppf)Cl₂·CH₂Cl₂ (52.92 mg, 0.065mmol, 0.10 equiv), The resulting solution was then stirred for overnightat 100° C. The resulting mixture was concentrated, the residue wasapplied onto a silica gel column with dichloromethane/methanol(1:0-10:1). This resulted in 120 mg (8.12%) of2-((2-(5-(((tert-butyldimethylsilyl)oxy)methyl)isoquinolin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(6-methylpyridin-3-yl)acetamideas a brown solid. LCMS (ES) [M+1]⁺ m/z 569.

Step 7

Into a 40 mL round-bottom flask were placed2-[[2-(5-[[(tert-butyldimethylsilyl)oxy]methyl]isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-N-(6-methylpyridin-3-yl)acetamide(120.00 mg, 0.211 mmol, 1.00 equiv), THF (3.00 mL) and Et₃N·3HF (170.05mg, 1.055 mmol, 5.00 equiv). The resulting solution was stirred for 12 hat room temperature. The pH value of the solution was adjusted to 7˜8with NH₃H₂O. The resulting mixture was concentrated and the crudeproduct was purified by Prep-HPLC with the following conditions: Column,SunFire Prep C18 OBD Column, 19*150 mm 5 um 10 nm; mobile phase, Water(0.1% FA) and ACN (48.0% ACN up to 53.0% in 7 min, hold 95.0% in 1 min,down to 48.0% in 1 min, hold 48.0% in 1 min); Detector, UV 220 nm. Thisresulted in 41.6 mg (43.38%) of2-({2-[5-(hydroxymethyl)isoquinolin-3-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methylpyridin-3-yl)acetamideas a white solid. LCMS (ES) [M+1]⁺ m/z 455. ¹H NMR (300 MHz, DMSO-d6) δ10.40 (s, 1H), 9.37 (s, 1H), 8.88 (s, 1H), 8.61 (d, J=2.6 Hz, 1H), 8.07(d, J=8.1 Hz, 1H), 7.90 (dd, J=8.4, 2.6 Hz, 1H), 7.82 (d, J=7.1 Hz, 1H),7.74-7.63 (m, 1H), 7.16 (d, J=8.5 Hz, 1H), 5.40 (br, 1H), 4.98 (d, J=4.2Hz, 2H), 4.51 (s, 2H), 3.39 (s, 3H), 3.23 (t, J=7.1 Hz, 2H), 2.90 (t,J=7.9 Hz, 2H), 2.38 (s, 3H), 2.09-1.97 (m, 2H).

Example 1.277 Synthesis ofN-(3-fluorophenyl)-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 271)

Compound 271 was synthesized similar to compound 142 by replacingcyclohexylamine with 3-fluoroaniline. LCMS (ES) [M+1]⁺ m/z: 381; ¹H-NMR(300 MHz, DMSO-d₆, ppm): δ 10.43 (s, 1H), 7.69-7.55 (m, 3H), 7.41-7.26(m, 2H), 6.93-6.80 (m, 1H), 4.36 (s, 2H), 3.61 (s, 3H), 3.32 (s, 3H),3.13 (t, J=7.2 Hz, 2H), 2.75 (t, J=7.8 Hz, 2H), 2.01-1.91 (m, 2H).

Example 1.278 Synthesis ofN-(3-methoxyphenyl)-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 272)

Compound 272 was synthesized similar to compound 142 by replacingcyclohexylamine with 3-methoxyaniline. LCMS (ES) [M+1]⁺ m/z: 393; ¹H-NMR(300 MHz, DMSO-d₆, ppm): δ 10.19 (s, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.58(d, J=1.2 Hz, 1H), 7.33 (t, J=2.1 Hz, 1H), 7.25-7.11 (m, 2H), 6.63-6.59(m, 1H), 4.35 (s, 2H), 3.69 (s, 3H), 3.61 (s, 3H), 3.31 (s, 3H), 3.13(t, J=7.2 Hz, 2H), 2.74 (t, J=7.8 Hz, 2H), 2.01-1.90 (m, 2H).

Example 1.279 Synthesis of(2R)-2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(pyridazin-4-yl)propanamide(Compound 273)

Compound 273 was synthesized similar to compound 108 by replacingcyclohexylamine with 4-pyridazinylamine and by replacing2-(tributylstannyl)pyridine with 3-(tributylstannyl)isoquinoline. LCMS(ES+): [M+H]⁺=426. ¹H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.62-9.55(m, 2H), 9.15 (s, 1H), 9.09 (d, J=6.2 Hz, 1H), 8.39-8.26 (m, 2H), 8.22(dd, J=6.2, 2.7 Hz, 1H), 7.96 (dddd, J=34.5, 8.1, 7.0, 1.2 Hz, 2H), 5.66(d, J=7.7 Hz, 1H), 3.54 (s, 3H), 3.47-3.29 (m, 2H), 3.17-3.06 (m, 2H),2.26-2.08 (m, 2H), 1.70 (d, J=7.1 Hz, 3H).

Example 1.280 Synthesis of(2R)-2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-[6-(trifluoromethyl)pyridin-3-yl]propanamide(Compound 274)

Compound 274 was synthesized similar to compound 108 by replacingcyclohexylamine with 6-trifluoropyridin-3-amine. LCMS (ES+): [M+H]⁺=426.¹H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.62-9.55 (m, 2H), 9.15 (s,1H), 9.09 (d, J=6.2 Hz, 1H), 8.39-8.26 (m, 2H), 8.22 (dd, J=6.2, 2.7 Hz,1H), 7.96 (dddd, J=34.5, 8.1, 7.0, 1.2 Hz, 2H), 5.66 (d, J=7.7 Hz, 1H),3.54 (s, 3H), 3.47-3.29 (m, 2H), 3.17-3.06 (m, 2H), 2.26-2.08 (m, 2H),1.70 (d, J=7.1 Hz, 3H).

Example 1.281 Synthesis ofN-(1-hydroxy-2-methylpropan-2-yl)-2-({2-[1-(3-hydroxypropyl)-1H-imidazol-4-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 275)

Step 1

Into a 100-mL round-bottom flask were placed ethylN-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinate(2.00 g, 7.415 mmol, 1.00 equiv), dioxane (20.00 mL, 236.082 mmol, 31.84equiv), water (2 mL), 1-(triphenylmethyl)imidazol-4-ylboronic acid (3.94g, 11.122 mmol, 1.50 equiv), K₃PO₄ (3.15 g, 14.830 mmol, 2.00 equiv) andPd(dppf)Cl₂ (0.54 g, 0.741 mmol, 0.10 equiv). The resulting solution wasstirred for 16 hr at 100° C. The resulting mixture was concentrated. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:3). This resulted in 0.88 g (21.83%) of ethylN-methyl-N-(2-(1-trityl-1H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycinateas a yellow solid. LCMS (ES) [M+1]⁺ m/z: 544.

Step 2

Into a 100-mL round-bottom flask were placed ethylN-methyl-N-(2-(1-trityl-1H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycinate(800.00 mg, 1.471 mmol, 1.00 equiv), THF (5.00 mL, 61.715 mmol, 41.94equiv), H₂O (5.00 mL, 277.542 mmol, 188.61 equiv) and NaOH (117.71 mg,2.943 mmol, 2.00 equiv). The resulting solution was stirred for 2 hr at25° C. The resulting solution was diluted with 20 mL of water. The pHvalue of the solution was adjusted to 6 with HCl (1 mol/L). The solidswere collected by filtration. This resulted in 640 mg (84.35%) ofN-methyl-N-(2-(1-trityl-1H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycineas an off-white solid. LCMS (ES) [M+1]⁺ m/z: 516.

Step 3

Into a 25-mL round-bottom flask were placedN-methyl-N-(2-(1-trityl-1H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycine(640.00 mg, 1.241 mmol, 1.00 equiv), DMF (10 mL),2-amino-2-methyl-1-propanol (110.64 mg, 1.241 mmol, 1.00 equiv), HATU(707.93 mg, 1.862 mmol, 1.50 equiv) and DIEA (481.26 mg, 3.724 mmol,3.00 equiv). The resulting solution was stirred for 2 hr at 25° C. Thecrude reaction mixture was filtered and subjected to reverse phasepreparative HPLC (Prep-C18, 20-45 uM, 120 g, Tianjin Bonna-AgelaTechnologies; gradient elution of 40% MeCN in water to 50% MeCN in waterover a 10 min period, water contains 0.1% NH₃H₂O). This resulted in (250mg, 34.33%)N-(1-hydroxy-2-methylpropan-2-yl)-2-(methyl(2-(1-trityl-1H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamideas a light yellow solid. LCMS (ES) [M+1]⁺ m/z: 587.

Step 4

Into a 25-mL round-bottom flask were placedN-(1-hydroxy-2-methylpropan-2-yl)-2-(methyl(2-(1-trityl-1H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide(250.00 mg, 0.426 mmol, 1.00 equiv), HCl (gas) in 1,4-dioxane (10.00mL). The resulting solution was stirred for 2 hr at 25° C. The solidswere collected by filtration. This resulted in 150 mg (92.43%) of2-((2-(1H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(1-hydroxy-2-methylpropan-2-yl)acetamidehydrochloride as a yellow solid. LCMS (ES) [M+1]⁺ m/z: 381.

Step 5

Into a 100-mL round-bottom flask were placed2-((2-(1H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(1-hydroxy-2-methylpropan-2-yl)acetamidehydrochloride (150.00 mg, 0.394 mmol, 1.00 equiv), dimethylformamide (10mL), DIEA (152.70 mg, 1.181 mmol, 3.00 equiv) andt-butyldimethylchlorosilane (71.23 mg, 0.473 mmol, 1.20 equiv). Theresulting solution was stirred for 16 hr at 25° C. The crude reactionmixture was filtered and subjected to reverse phase preparative HPLC(Prep-C18, 20-45 uM, 120 g, Tianjin Bonna-Agela Technologies; gradientelution of 50% MeCN in water to 60% MeCN in water over a 10 min period,water contains 0.1% NH₃H₂O) to provide-((2-(1H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)acetamideas a light yellow solid (120 mg, 66.43%). LCMS (ES) [M+1]⁺ m/z: 459.

Step 6

Into a 100 mL round-bottom flask were placed2-((2-(1H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)acetamide(120.00 mg, 0.262 mmol, 1.00 equiv), dimethylformamide (10 mL),3-bromopropanol (72.73 mg, 0.523 mmol, 2.00 equiv), K₂CO₃ (108.47 mg,0.785 mmol, 3.00 equiv). The resulting solution was stirred for 48 hr at70° C. The residue was applied onto a silica gel column withdichloromethane/methanol (10:1). The collected fractions were combinedand concentrated. This resulted in 80 mg (59.17%) ofN-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-2-((2-(1-(3-hydroxypropyl)-1H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a yellow solid. LCMS (ES) [M+1]⁺ m/z: 517.

Step 7

Into a 100-mL round-bottom flask were placedN-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-2-((2-(1-(3-hydroxypropyl)-1H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(80.00 mg, 0.155 mmol, 1.00 equiv), tetrahydrofuran (5 mL), TBAF (4.05mg, 0.015 mmol, 0.10 equiv). The resulting solution was stirred for 2 hrat 25° C. The crude reaction mixture was filtered and subjected toreverse phase preparative HPLC (Prep-C18, 20-45 uM, 120 g, TianjinBonna-Agela Technologies; gradient elution of 25% MeCN in water to 35%MeCN in water over a 10 min period, water contains 0.1% NH₃H₂O). Thisresulted in (18.6 mg, 29.85%)N-(1-hydroxy-2-methylpropan-2-yl)-2-((2-(1-(3-hydroxypropyl)-1H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas an off-white solid LCMS (ES) [M+1]⁺ m/z: 403. ¹H NMR (300 MHz,DMSO-d6) δ 7.77 (d, J=1.4 Hz, 1H), 7.63 (d, J=1.4 Hz, 1H), 7.47 (s, 1H),4.95 (t, J=5.9 Hz, 1H), 4.65 (t, J=5.1 Hz, 1H), 4.10 (s, 2H), 4.05 (t,J=7.0 Hz, 2H), 3.49-3.35 (m, 4H), 3.21 (s, 3H), 3.08 (t, J=7.2 Hz, 2H),2.73 (t, J=7.8 Hz, 2H), 1.92 (dt, J=13.2, 7.3 Hz, 4H), 1.18 (s, 6H).

Example 1.282 Synthesis of2-[(2-{4-[(1-hydroxy-2-methylpropan-2-yl)oxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(2-methoxypyrimidin-5-yl)acetamide(Compound 276)

Compound 276 was synthesized similar to compound 144 by replacingcyclohexylamine with 2-methoxypyrimidin-5-amine and replacing4-[2-(oxan-2-yloxy)ethoxy]-2-(trimethylstannyl)pyridine with4-[[2-methyl-1-(oxan-2-yloxy)propan-2-yl]oxy]-2-(trimethylstannyl)pyridine.LCMS (ES) [M+1]⁺ m/z: 480; ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 10.49 (s,1H), 8.74 (s, 2H), 8.43 (d, J=5.4 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.03(dd, J=5.7, 2.7 Hz, 1H), 4.67 (s, 1H), 4.42 (s, 2H), 3.87 (s, 3H), 3.80(s, 2H), 3.24 (s, 3H), 3.22 (t, J=7.2 Hz, 2H), 2.84 (t, J=7.8 Hz, 2H),2.07-1.99 (m, 2H), 1.16 (s, 6H).

Example 1.283 Synthesis of(2R)—N-(3-fluorophenyl)-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 277)

Compound 277 was synthesized similar to compound 108 by replacing1-cyclohexylamine with 3-fluoroaniline and by replacing2-(tributylstannyl)pyridine with 1-methyl-4-(tributylstannyl)imidazole.LCMS (ES) [M+1]⁺ m/z: 395; ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 10.60 (s,1H), 8.14 (s, HCOOH), 7.78 (d, J=1.2 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H),7.66 (dt, J=12.0, 2.4 Hz, 1H), 7.45-7.40 (m, 1H), 7.32-7.24 (m, 1H),6.83 (td, J=8.4, 2.7 Hz, 1H), 5.26 (q, J=7.2 Hz, 1H), 3.68 (s, 3H),3.22-3.14 (m, 1H), 3.13 (s, 3H), 3.08-2.97 (m, 1H), 2.86-2.66 (m, 2H),2.06-1.86 (m, 2H), 1.43 (d, J=7.2 Hz, 3H).

Example 1.284 Synthesis of(2R)—N-(3-methoxyphenyl)-2-{methyl[2-(1-methyl-1H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 278)

Compound 278 was synthesized similar to compound 108 by replacing1-cyclohexylamine with 3-methoxyaniline and by replacing2-(tributylstannyl)pyridine with 1-methyl-4-(tributylstannyl)imidazole.LCMS (ES) [M+1]⁺ m/z: 407; ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 10.58 (s,1H), 8.17 (s, HCOOH), 7.81 (d, J=1.5 Hz, 1H), 7.72 (d, J=1.2 Hz, 1H),7.31 (t, J=2.1 Hz, 1H), 7.29-7.23 (m, 1H), 7.14 (t, J=8.1 Hz, 1H),6.60-6.55 (m, 1H), 5.29 (q, J=7.2 Hz, 1H), 3.69 (s, 3H), 3.63 (s, 3H),3.21-3.10 (m, 1H), 3.13 (s, 3H), 3.06-2.96 (m, 1H), 2.86-2.66 (m, 2H),2.03-1.86 (m, 2H), 1.42 (d, J=7.2 Hz, 3H).

Example 1.285 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(3-methoxyphenyl)acetamide(Compound 279)

Step 1

Into a 250 mL three necked round bottom flask purged and maintained withan inert atmosphere of nitrogen, was placed ethylN-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinate(2.0 g, 7.4 mmol, 1.00 equiv), toluene (40.00 mL),4-fluoro-2-(tributylstannyl)pyridine (4.3 g, 11.1 mmol, 1.5 equiv),Pd(PPh₃)₄ (780 mg, 0.74 mmol, 0.10 equiv). The mixture was stirred for36 h at 110° C. in oil bath. The reaction mixture was cooled to roomtemperature, concentrated to remove the solvent; the residue waspurified by silica gel column with dichloromethane/methanol (25:1). Thisresulted in 1.4 g (57% yield) of ethylN-(2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinateas yellow solid. LCMS (ES) [M+1]+ m/z: 331.

Step 2

Into a 250 mL round-bottom flask, was placed ethylN-(2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinate(1.4 g, 4.2 mmol, 1 equiv), tetrahydrofuran (30 mL), water (15 mL),lithiumol (0.21 g, 8.4 mmol, 2.00 equiv). The resulting solution wasstirred for 2 hr at 25° C. The resulting mixture was concentrated. Theresulting solution was diluted with 50 mL of water. The pH value of thesolution was adjusted to 4 with HCl (1 mol/L). The solids were collectedby filtration. This resulted in 0.68 g (53%) ofN-(2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycineas an off-white solid. LCMS (ES) [M+1]⁺ m/z 303.

Step 3

Into a 8 mL vial were placed m-anisidine (102 mg, 0.83 mmol, 1.00equiv), DMF (5 mL),3-[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]butanoicacid (250 mg, 0.83 mmol, 1.00 equiv) and DIEA (322 mg, 2.49 mmol, 3.00equiv). This was followed by the addition of T3P (317 mg, 1.00 mmol,1.20 equiv) at 0° C. The resulting solution was stirred for 2 hr at 25°C. The reaction was then quenched by the addition of 50 mL of water. Theresulting solution was extracted with 3×100 mL of ethyl acetate and theorganic layers combined. The resulting mixture was washed with 3×100 mlof brine and concentrated under vacuum. The residue was applied onto asilica gel column with dichloromethane/methanol (20:1). This resulted in180 mg (53.25%) of2-[[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-N-(3-methoxyphenyl)acetamideas light brown oil. LCMS (ES) [M+1]⁺ m/z 408.

Step 2

Into a 50 mL 3-necked round-bottom flask were placed ethylene glycol(114 mg, 1.84 mmol, 5.00 equiv), THE (5 mL). This was followed by theaddition of NaH (18 mg, 0.74 mmol, 2.00 equiv) at 0° C. The resultingsolution was stirred for 30 min at 0° C. To this was added2-[[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-N-(3-methoxyphenyl)acetamide(150 mg, 0.37 mmol, 1.00 equiv) at 0° C. The resulting solution wasstirred for 1 hr at 25° C. The reaction was then quenched by theaddition of 30 mL of water. The resulting solution was extracted with2×50 mL of ethyl acetate, the organic layers were combined andconcentrated under vacuum. The residue was dissolved in 5 mL of MeOH.The crude product was purified by Prep-HPLC with the followingconditions (Prep-HPLC-001): Column, Sunfire Prep C18 OBD Column, 50*250mm, 5 μm 10 nm; mobile phase, Water (0.1% FA) and ACN (5% PhaseB up to35% in 15 min). This resulted in 61.0 mg (36.86%) of2-([2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(3-methoxyphenyl)acetamideas a white solid. LCMS (ES) [M+1]⁺ m/z 450. ¹H NMR (300 MHz, DMSO-d₆)δ10.22 (s, 1H), 8.46 (d, J=5.7 Hz, 1H), 8.14 (s, 0.4HCOOH), 7.80 (d,J=2.5 Hz, 1H), 7.30 (t, J=2.2 Hz, 1H), 7.19 (t, J=8.0 Hz, 1H), 7.15-7.08(m, 1H), 7.04 (dd, J=5.7, 2.6 Hz, 1H), 6.67-6.57 (m, 1H), 4.90 (t, J=5.4Hz, 1H), 4.44 (s, 2H), 4.03 (t, J=4.7 Hz, 2H), 3.69 (s, 3H), 3.69-3.64(m, 2H), 3.37 (s, 3H), 3.21 (t, J=7.3 Hz, 2H), 2.85 (t, J=7.8 Hz, 2H),2.05-1.93 (m, 2H).

Example 1.286 Synthesis ofN-(3-fluorophenyl)-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 280)

Step 1

Into a 100-mL round-bottom flask were placed a mixture of ethylN-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinate(3.00 g, 11.1 mmol, 1.00 equiv), MeOH (30.0 mL), H2O (6.00 mL), NaOH(889 mg, 0.022 mmol, 2.00 equiv). The resulting solution was stirred for2 hours at room temperature. The resulting mixture was concentrated. Theresulting solution was diluted with 50 mL of H₂O. The pH value of thesolution was adjusted to 4 with HCl (2 mol/L). The solids were collectedby filtration and concentrated. This resulted in 1.3 g (48.36%) ofN-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycineas a white solid. LCMS (ES) [M+1]+ m/z 270.

Step 2

Into a 50-mL round-bottom flask were was placedN-(2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycine (3.7g, 15.29 mmol, 1.00 equiv), DMF (30.00 mL), HATU (6.97 g, 18.34 mmol,1.20 equiv), DIEA (5.92 g, 45.86 mmol, 3.00 equiv), 3-fluoroaniline(2.04 g, 18.34 mmol, 1.20 equiv). The resulting solution was stirred for2 hr at 25° C. The resulting solution was extracted with 3×100 mL ofethyl acetate and the organic layers combined. The resulting mixture waswashed with 3×100 of brine and concentrated under vacuum. The residuewas applied onto a silica gel column with DCM/MeOH (10:1). This resultedin 3.20 g (62.50%) of2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(3-fluorophenyl)acetamideas yellow solid. LCMS (ES) [M+1]⁺ m/z 335.

Step 3

Into a 40-mL vial purged and maintained with an inert atmosphere ofnitrogen were placed 1-[(2-chloropyridin-4-yl)oxy]-2-methylpropan-2-ol(1.00 g, 4.96 mmol, 1.00 equiv), Sn₂Me₆ (1.71 g, 5.21 mmol, 1.05 equiv),toluene (30 mL), Pd(PPh₃)₄ (0.57 g, 0.50 mmol, 0.10 equiv). Theresulting solution was stirred for 2 hr at 100° C. To this was added2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(3-fluorophenyl)acetamide(1.16 g, 3.471 mmol, 0.7 equiv), Pd(PPh₃)₄ (0.57 g, 0.496 mmol, 0.10equiv). The resulting solution was stirred for overnight at 100° C. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with dichloromethane/methanol (20:1). The crudeproduct was purified by Prep-HPLC with the following conditions: Column,Sunfire Prep C18 OBD Column, 50*250 mm, 5 μm 10 nm; mobile phase A,Water (0.1% FA) and mobile phase B, AcCN (5% mobile Phase B up to 40% in15 min); This resulted in 48.2 mg (2.09%) ofN-(3-fluorophenyl)-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamideas a white solid. LCMS (ES) [M+1]⁺ m/z 466. ¹H NMR (300 MHz, DMSO-d₆) δ10.43 (s, 1H), 8.44 (d, J=5.6 Hz, 1H), 7.78 (d, J=2.5 Hz, 1H), 7.60-7.49(m, 1H), 7.37-7.24 (m, 2H), 7.02 (dd, J=5.6, 2.6 Hz, 1H), 6.92-6.80 (m,1H), 4.65 (s, 1H), 4.44 (s, 2H), 3.80 (s, 2H), 3.36 (s, 3H), 3.21 (t,J=7.3 Hz, 2H), 2.84 (t, J=7.8 Hz, 2H), 2.07-1.99 (m, 2H), 1.17 (s, 6H).

Example 1.287 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetamide(Compound 281)

Compound 281 was synthesized similar to compound 135 replacingoxolan-3-amine with 5-amino-1-methylpyridin-2-one. LCMS (ES) [M+1]⁺ m/z:421; ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 10.01 (s, 1H), 8.46 (d, J=5.6 Hz,1H), 8.07 (d, J=2.8 Hz, 1H), 7.78 (d, J=2.6 Hz, 1H), 7.40 (dd, J=9.7,2.9 Hz, 1H), 7.02 (dd, J=5.6, 2.6 Hz, 1H), 6.38 (d, J=9.6 Hz, 1H), 4.35(s, 2H), 3.83 (s, 3H), 3.37 (s, 3H), 3.35 (s, 3H), 3.20 (t, J=7.3 Hz,2H), 2.84 (t, J=7.8 Hz, 2H), 2.04-1.99 (m, 2H).

Example 1.288 Synthesis of2-[(2-{2H,3H-[1,4]dioxino[2,3-c]pyridin-7-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(3-fluorophenyl)acetamide(Compound 282)

Compound 282 was synthesized similar to compound 280 by replacing1-[(2-chloropyridin-4-yl)oxy]-2-methylpropan-2-ol with7-bromo-2H,3H-[1,4]dioxino[2,3-c]pyridine. LCMS (ES) [M+1]⁺ m/z: 436;¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 10.42 (s, 1H), 8.16 (0.3 HCOOH), 8.14(s, 1H), 7.77 (s, 1H), 7.55 (dd, J=12.0, 2.1 Hz, 1H), 7.38-7.25 (m, 2H),6.92-6.80 (m, 1H), 4.45 (s, 2H), 4.41 (s, 4H), 3.35 (s, 3H), 3.18 (t,J=7.3 Hz, 2H), 2.80 (t, J=7.8 Hz, 2H), 2.04-1.94 (m, 2H).

Example 1.289 Synthesis of2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-[5-(trifluoromethoxy)pyridin-3-yl]acetamide(Compound 283)

Compound 283 was synthesized similar to compound 135 by replacing of4-methoxy-2-(tributylstannyl)pyridine with3-(trimethylstannyl)isoquinoline and replacing oxolan-3-amine with3-amino-5-trifluoromethoxypyridine. LCMS (ES) [M+1]⁺ m/z: 495. ¹H NMR(300 MHz, Chloroform-d) δ 10.96 (s, 1H), 9.33 (s, 1H), 8.80 (d, J=2.1Hz, 1H), 8.71 (s, 1H), 8.33 (d, J=2.5 Hz, 1H), 8.23 (s, 1H), 8.14 (d,J=7.7 Hz, 1H), 7.78-7.69 (m, 3H), 4.51 (s, 2H), 3.44 (s, 3H), 3.24 (m,2H), 2.88 (m, 2H), 2.05 (m, 2H).

Example 1.290 Synthesis of 22-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(5-methylpyrazin-2-yl)acetamide(Compound 284)

Compound 284 was synthesized similar to compound 44 by replacing oftert-butylamine with 5-methylpyrazin-2-amine. LCMS (ES) [M+1]⁺ m/z:436.2. ¹H NMR (300 MHz, Chloroform-d) δ 9.59 (br, 1H), 9.40 (s, 1H),8.62-8.61 (m, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 6.89-6.88 (s, 1H),4.43-4.42 (m, 2H), 4.21-4.20 (m, 2H), 4.01-4.00 (m, 2H), 3.28 (s, 3H),3.03-3.01 (m, 2H), 2.76-2.75 (m, 2H), 2.49 (s, 3H), 2.13-4.11 (m, 2H).

Example 1.291 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methoxypyridazin-3-yl)acetamide(Compound 285)

Compound 285 was synthesized similar to compound 44 by replacing oftert-butylamine with 6-methoxypyridazin-3-amine. LCMS (ES) [M+1]⁺ m/z:452. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 11.15 (s, 1H), 8.41 (d, J=5.7 Hz,1H), 8.21 (d, J=9.6 Hz, 1H), 8.15 (HCOOH), 7.74 (d, J=2.7 Hz, 1H), 7.22(d, J=9.6 Hz, 1H), 6.98 (dd, J=5.7, 2.7 Hz, 1H), 4.85 (br, 1H), 4.55 (s,2H), 4.00-3.97 (m, 5H), 3.66 (t, J=4.8 Hz, 2H), 3.36 (s, 3H), 3.21 (t,J=7.2 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.07-1.96 (m, 2H).

Example 1.292 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methylpyridazin-3-yl)acetamide(Compound 286)

Compound 286 was synthesized similar to compound 44 by replacingtert-butylamine with 6-methypyridazin-3-amine. LCMS (ES) [M+1]⁺ m/z:436. ¹H NMR (300 MHz, DMSO-d₆, ppm δ 11.23 (s, 1H), 8.40 (d, J=5.6 Hz,1H), 8.15 (d, 9.4 Hz), 8.14 (HCOOH), 7.71 (d, J=2.6 Hz, 1H), 7.52 (d,J=9.2 Hz, 1H), 6.96 (dd, J=5.6, 2.5 Hz, 1H), 4.86 (s, 1H), 4.55 (s, 2H),3.97 (t, J=4.8 Hz, 2H), 3.63 (s, 2H), 3.35 (s, 2H), 3.21 (t, J=7.5 Hz,2H), 2.83 (t, J=7.9 Hz, 2H), 2.55 (s, 3H), 2.06-1.95 (m, 2H).

Example 1.293 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)acetamide(Compound 287)

Compound 287 was synthesized similar to compound 135 by replacingoxolan-3-amine with 4-amino-1-methylpyridin-2-one hydrochloride. LCMS(ES) [M+1]⁺ m/z: 421; ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 10.36 (s, 1H),8.44 (d, J=5.6 Hz, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.58 (d, J=7.4 Hz, 1H),7.00 (dd, J=5.6, 2.6 Hz, 1H), 6.71 (d, J=2.2 Hz, 1H), 6.39 (dd, J=7.4,2.3 Hz, 1H), 4.42 (s, 2H), 3.80 (s, 3H), 3.36 (s, 3H), 3.33 (s, 3H),3.20 (t, J=7.3 Hz, 2H), 2.84 (t, J=7.7 Hz, 2H), 2.04-1.99 (m, 2H).

Example 1.294 Synthesis of2-[methyl(2-{1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]-N-[6-(trifluoromethyl)pyridin-3-yl]acetamide(Compound 288)

Compound 288 was synthesized similar to compound 135 by replacing4-methoxy-2-(tributylstannyl)pyridine with1-(oxan-2-yl)-5-(tributylstannyl)-1H-pyrazolo[3,4-c]pyridine and byreplacing oxolan-3-amine with 6-trifluoropyridin-3-amine. LCMS (ES+):[M+H]⁺=469.1. ¹H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 9.20 (s, 1H),9.11 (s, 1H), 9.05 (s, 1H), 8.40 (d, J=8.7 Hz, 1H), 8.29 (s, 1H), 7.86(d, J=8.6 Hz, 1H), 4.83 (s, 2H), 3.61 (s, 2H), 3.35-3.32 (m, 2H),3.11-3.04 (m, 2H), 2.18-2.05 (m, 2H).

Example 1.295 Synthesis ofN-(4-fluorophenyl)-2-[methyl(2-{1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 289)

Compound 289 was synthesized similar to compound 135 by replacing4-methoxy-2-(tributylstannyl)pyridine with1-(oxan-2-yl)-5-(tributylstannyl)-1H-pyrazolo[3,4-c]pyridine and byreplacing oxolan-3-amine with 4-fluoroaniline. LCMS (ES+): [M+H]⁺=418.1.¹H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.15 (s, 1H), 8.88 (s, 1H),8.20 (s, 1H), 7.73-7.67 (m, 2H), 7.18-7.12 (m, 2H), 4.60 (s, 2H), 3.51(s, 3H), 3.26-3.24 (m, 2H), 3.01-2.96 (m, 2H), 2.12-2.03 (m, 2H).

Example 1.296 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(5-methoxypyrazin-2-yl)acetamide(Compound 290)

Compound 290 was synthesized similar to compound 44 by replacingtert-butylamine with 5-methoxypyrazin-2-amine. LCMS (ES) [M+1]⁺ m/z:452. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 10.79 (s, 1H), 8.81 (s, 1H), 8.41(d, J=5.5 Hz, 1H), 8.11 (d, J=1.5 Hz, 1H), 7.73 (d, J=2.6 Hz, 1H), 6.97(dd, J=5.6, 2.6 Hz, 1H), 4.85 (br, 1H), 4.58 (s, 2H), 4.00 (t, J=4.7 Hz,2H), 3.85 (s, 3H), 3.71-3.63 (m, 2H), 3.41 (s, 3H), 3.33-3.15 (m, 2H),2.83 (t, J=7.9 Hz, 2H), 2.08-1.88 (m, 2H).

Example 1.297 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(2-methylpyrimidin-5-yl)acetamide(Compound 291)

Compound 291 was synthesized similar to compound 44 by replacingtert-butylamine with 2-methylpyrimidin-5-amine. LCMS (ES) [M+1]⁺ m/z:436. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ10.73 (s, 1H), 8.89 (s, 2H), 8.42(d, J=5.6 Hz, 1H), 8.36 (s, 1H), 7.76 (d, J=2.5 Hz, 1H), 7.01 (dd,J=5.7, 2.6 Hz, 1H), 4.45 (s, 2H), 4.04 (t, J=4.8 Hz, 2H), 3.70 (q, J=5.0Hz, 2H),3.36 (s, 3H), 3.22 (t, J=7.3 Hz, 2H), 2.84 (t, J=7.8 Hz, 2H),2.55 (s, 3H), 2.15-1.96 (m, 2H).

Example 1.298 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(3-methylphenyl)acetamide(Compound 292)

Compound 292 was synthesized similar to compound 44 by replacingtert-butylamine with m-toluidine. LCMS (ES) [M+1]⁺ m/z: 434. ¹H NMR (300MHz, DMSO-d₆, ppm) δ 10.12 (s, 1H), 8.44 (d, J=5.6 Hz, 1H), 7.79 (d,J=2.5 Hz, 1H), 7.46-7.33 (m, 2H), 7.19-7.13 (m, 1H), 7.00 (dd, J=5.6,2.5 Hz, 1H), 6.85 (d, J=7.5 Hz, 1H), 4.88 (t, J=5.4 Hz, 1H), 4.42 (s,2H), 4.02 (t, J=4.7 Hz, 2H), 3.66 (q, J=5.0 Hz, 2H), 3.36 (s, 3H), 3.20(t, J=7.3 Hz, 2H), 2.83 (t, J=7.9 Hz, 2H), 2.25 (s, 3H), 2.07-1.96 (m,2H).

Example 1.299 Synthesis of2-({2-[4-(2-aminoethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(3-fluorophenyl)acetamide(Compound 293)

Step 1

Into a 50-mL 3-necked round-bottom flask were placed tert-butylN-(2-hydroxyethyl)carbamate (1.47 g, 9.12 mmol, 1.20 equiv) and THE (10mL). This was followed by the addition of NaH (0.22 g, 9.17 mmol, 1.20equiv) at 0° C. The resulting solution was stirred for 30 min at 0° C.and was added 2-chloro-4-fluoropyridine (1.00 g, 7.60 mmol, 1.00 equiv).After stirred for 2 hr at 25° C., the reaction was quenched by theaddition of 50 mL of water. The resulting mixture was extracted with3×100 mL of ethyl acetate, the organic layers were combined, washed with3×100 ml of brine, dried over anhydrous sodium sulfate. The solids werefiltered out and the filtrate was concentrated under vacuum. Thisresulted in 1.5 g (49.34%) of tert-butylN-[2-[(2-chloropyridin-4-yl)oxy]ethyl]carbamate as yellow oil. LCMS (ES)[M+1]⁺ m/z 273.

Step 2. Into a 40-mL vial purged and maintained with an inert atmosphereof nitrogen were placed tert-butylN-[2-[(2-chloropyridin-4-yl)oxy]ethyl]carbamate (1.00 g, 3.67 mmol, 1.00equiv), Toluene (30 mL), Sn₂Me₆ (1.26 g, 3.85 mmol, 1.05 equiv) andPd(PPh₃)₄ (0.42 mg, 0.36 mmol, 0.1 equiv). The resulting solution wasstirred for 4 h at 100° C. To this was addedC2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(3-fluorophenyl)acetamide(0.86 g, 2.57 mmol, 0.7 equiv), Pd(PPh₃)₄ (0.42 g, 0.36 mmol, 0.1equiv). After stirred for overnight at 100° C., the mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with dichloromethane/methanol (20:1). This resulted in 300 mg(15.25%) of tert-butylN-[2-([2-[4-([[(3-fluorophenyl)carbamoyl]methyl](methyl)amino)-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]pyridin-4-yl]oxy)ethyl]carbamateas brown oil. LCMS (ES) [M+1]⁺ m/z 537.Step 3

Into a 50-mL round-bottom flask were placed tert-butylN-[2-([2-[4-([[(3-fluorophenyl)carbamoyl]methyl](methyl)amino)-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]pyridin-4-yl]oxy)ethyl]carbamate(300 mg, 1.00 equiv), DCM (2 mL) and HCl (gas) in 1,4-dioxane (2 mL).The resulting solution was stirred for 2 hr at 25° C. The resultingmixture was concentrated under vacuum. The residue was dissolved in 5 mLof MeOH. The crude product was purified by Prep-HPLC with the followingconditions: Column, Sunfire Prep C18 OBD Column, 50*250 mm, 5 μm 10 nm;mobile phase A, Water (0.1% FA) and mobile phase B, AcCN (5% mobilePhase B up to 35% in 15 min); Detector, UV 254 nm. This resulted in 60.5mg of2-({2-[4-(2-aminoethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(3-fluorophenyl)acetamideas a white solid. LCMS (ES) [M+1]⁺ m/z 437. ¹H NMR (300 MHz, DMSO-d₆): δ10.56 (s, 1H), 8.69 (d, J=6.0 Hz, 1H), 8.07 (br, 3H), 7.96 (d, J=2.6 Hz,1H), 7.65-7.54 (m, 1H), 7.44-7.27 (m, 3H), 6.97-6.84 (m, 1H), 4.65 (s,2H), 4.37 (s, 2H), 3.48 (s, 3H), 3.26 (s, 4H), 3.00 (t, J=7.9 Hz, 2H),2.08-3.02 (m, 2H).

Example 1.300 Synthesis of2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(3-fluorophenyl)acetamide(Compound 294)

Compound 294 was synthesized similar to compound 348 replacingtert-butylamine with 3-fluoroaniline. LCMS (ES) [M+1]⁺ m/z: 465. ¹H NMR(300 MHz, DMSO-d₆) δ 10.44 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.18 (s,1H), 7.75 (d, J=2.5 Hz, 1H), 7.60-7.50 (m, 1H), 7.38-7.25 (m, 2H), 7.00(dd, J=5.6, 2.6 Hz, 1H), 6.93-6.80 (m, 1H), 4.43 (s, 2H), 4.07 (t, J=5.5Hz, 2H), 3.37 (s, 3H), 3.21 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H),2.59 (t, J=5.5 Hz, 2H), 2.21 (s, 6H), 2.06-1.96 (m, 2H).

Example 1.301 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(5-methoxypyrimidin-2-yl)acetamide(Compound 295)

Compound 295 was synthesized similar to compound 44 replacingtert-butylamine with 5-methoxypyrimidin-2-amine. LCMS (ES) [M+1]⁺ m/z:452. ¹H NMR (300 MHz, DMSO-d₆) δ 10.67 (s, 1H), 8.47-8.39 (m, 3H), 7.77(d, J=2.6 Hz, 1H), 6.98 (dd, J=5.6, 2.6 Hz, 1H), 4.88 (s, 1H), 4.62 (s,2H), 4.02 (t, J=4.7 Hz, 2H), 3.88 (s, 3H), 3.67 (t, J=4.7 Hz, 2H), 3.33(s, 3H), 3.19 (t, J=7.4 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.15-1.96 (m,2H).

Example 1.302 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(1-methyl-1H-pyrazol-4-yl)acetamide(Compound 296)

Compound 296 was synthesized similar to compound 44 replacingtert-butylamine with 1-methylpyrazol-4-amine. LCMS (ES) [M+1]⁺ m/z: 424.¹H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.46 (d, J=5.7 Hz, 1H), 7.84(s, 1H), 7.77 (d, J=2.5 Hz, 1H), 7.40 (s, 1H), 7.02 (dd, J=5.7, 2.3 Hz,1H), 4.92 (t, J=5.4 Hz, 1H), 4.35 (s, 2H), 4.06 (t, J=4.8 Hz, 2H), 3.76(s, 3H), 3.72 (d, J=5.0 Hz, 2H), 3.32 (s, 3H), 3.19 (t, J=7.3 Hz, 2H),2.83 (t, J=7.8 Hz, 2H), 2.06-1.95 (m, 2H).

Example 1.303 Synthesis of2-({2-[6-(hydroxymethyl)isoquinolin-3-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methylpyridin-3-yl)acetamide(Compound 297)

Compound 297 was synthesized similar to compound 270 replacing5-[[(tert-butyldimethylsilyl)oxy]methyl]-3-(trimethylstannyl)isoquinolinewith6-(((tert-butyldimethylsilyl)oxy)methyl)-3-(trimethylstannyl)isoquinoline.LCMS (ES) [M+1]⁺ m/z: 455. ¹H NMR (300 MHz, DMSO-d6) δ 10.51 (s, 1H),9.33 (s, 1H), 8.69 (d, J=2.3 Hz, 2H), 8.13 (d, J=8.6 Hz, 1H), 7.96 (dd,J=8.4, 2.6 Hz, 1H), 7.70-7.64 (m, 2H), 7.18 (d, J=8.4 Hz, 1H), 5.49 (t,J=5.5 Hz, 1H), 4.68 (d, J=5.3 Hz, 2H), 4.49 (s, 2H), 3.45 (s, 3H),3.29-3.22 (m, 2H), 2.96-2.85 (m, 2H), 2.39 (s, 3H), 2.11-2.00 (m, 2H).

Example 1.304 Synthesis of2-{[2-(5-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6-methylpyridin-3-yl)acetamide(Compound 298)

Compound 298 was synthesized similar to Compound 24 by replacing2-tributylstannylpyridine with 5-fluoro-2-(tributylstannyl)pyridine andby replacing tert-bytylamine with 6-methylpyridin-3-amine. LCMS (ES+):[M+H]⁺=393.1. ¹H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.75 (d, J=2.8Hz, 1H), 8.69 (d, J=2.6 Hz, 1H), 8.51 (dd, J=8.9, 4.6 Hz, 1H), 7.98-7.87(m, 2H), 7.25 (d, J=8.4 Hz, 1H), 4.64 (s, 2H), 3.49 (s, 3H), 3.27-3.24(m, 2H), 3.00-2.95 (m, 2H), 2.42 (s, 3H), 2.12-2.03 (m, 2H).

Example 1.305 Synthesis ofN-tert-butyl-2-{[2-(5-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 299)

Compound 299 was synthesized similar to Compound 24 by replacing2-tributylstannylpyridine with 5-fluoro-2-(tributylstannyl)pyridine.LCMS (ES+): [M+H]⁺=358.1. ¹H NMR (400 MHz, dmso) δ 8.79 (d, J=2.8 Hz,1H), 8.55 (dd, J=8.8, 4.6 Hz, 1H), 8.02 (td, J=8.7, 2.9 Hz, 1H), 7.88(s, 1H), 4.30 (s, 2H), 3.40 (s, 3H), 3.22-3.18 (m, 2H), 3.01-2.93 (m,2H), 2.12-2.01 (m, 2H), 1.24 (s, 9H).

Example 1.306 Synthesis ofN-tert-butyl-2-{[2-(5-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 300)

Compound 300 was synthesized similar to Compound 24 by replacing2-tributylstannylpyridine with 5-chloro-2-(tributylstannyl)pyridine.LCMS (ES+): [M+H]⁺=374. ¹H NMR (400 MHz, DMSO-d6) δ 8.71 (dd, J=2.5, 0.7Hz, 1H), 8.38 (dd, J=8.5, 0.7 Hz, 1H), 8.03 (dd, J=8.5, 2.5 Hz, 1H),7.68 (s, 1H), 4.15 (s, 2H), 3.27 (s, 3H), 3.17-3.10 (m, 2H), 2.86-2.79(m, 2H), 2.04-1.94 (m, 2H), 1.23 (s, 9H).

Example 1.307 Synthesis ofN-tert-butyl-2-[methyl(2-{[1,3]thiazolo[4,5-c]pyridin-6-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 301)

Compound 301 was synthesized similar to compound 245 replacing2-chloro-4-(oxetan-3-yloxy)pyridine with6-bromo-[1,3]thiazolo[4,5-c]pyridine. LCMS (ES) [M+1]⁺ m/z: 397. ¹H NMR(300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.42 (d, J=0.9 Hz, 1H), 9.25 (d,J=0.9 Hz, 1H), 8.14 (0.5 HCOOH), 7.79 (s, 1H), 4.18 (s, 2H), 3.34 (s,3H), 3.18 (t, J=7.3 Hz, 2H), 2.86 (t, J=7.8 Hz, 2H), 2.05-1.99 (m, 2H),1.22 (s, 9H).

Example 1.308 Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methylpyridin-3-yl)acetamide(Compound 302)

Compound 302 was synthesized similar to compound 210 replacing5-amino-2-methoxypyridine with 6-methylpyridin-3-amine. LCMS (ES) [M+1]⁺m/z: 463. ¹H NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H), 8.60 (d, J=2.6 Hz,1H), 8.45 (d, J=5.7 Hz, 1H), 8.14 (s, HCOOH), 7.88 (dd, J=8.4, 2.6 Hz,1H), 7.79 (d, J=2.5 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.05 (dd, J=5.8,2.6 Hz, 1H), 4.73 (s, 1H), 4.43 (s, 2H), 3.81 (s, 2H), 3.38 (s, 3H),3.22 (t, J=7.2 Hz, 2H), 2.85 (t, J=7.8 Hz, 2H), 2.39 (s, 3H), 2.04-1.96(m, 2H), 1.17 (s, 6H).

Example 1.309 Synthesis ofN-tert-butyl-2-{[2-(5-fluoro-4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 303)

Compound 303 was synthesized similar to compound 24 by replacing2-tributylstannylpyridine with5-fluoro-4-methyl-2-(tributylstannyl)pyridine. LCMS (ES+): [M+H]⁺=372.2.¹H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=1.1 Hz, 1H), 8.30 (dd, J=6.5, 0.9Hz, 1H), 7.69 (s, 1H), 4.14 (s, 2H), 3.27 (s, 3H), 3.17-3.11 (m, 2H),2.83-2.76 (m, 2H), 2.37 (dd, J=1.7, 0.7 Hz, 3H), 2.02-1.93 (m, 2H), 1.22(s, 9H).

Example 1.310 Synthesis ofN-(6-methoxypyridin-3-yl)-2-[methyl(2-{[1,3]thiazolo[4,5-c]pyridin-6-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 304)

Compound 304 was synthesized similar to compound 258 replacing3-chloro-2,6-naphthyridine with 6-bromo-[1,3]thiazolo[4,5-c]pyridine.LCMS (ES) [M+1]⁺ m/z: 448. ¹H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H),9.55 (s, 1H), 9.38 (d, J=0.9 Hz, 1H), 9.11 (d, J=0.9 Hz, 1H), 8.39 (d,J=2.6 Hz, 1H), 7.92 (dd, J=8.9, 2.7 Hz, 1H), 6.78 (d, J=8.9 Hz, 1H),4.44 (s, 2H), 3.79 (s, 3H), 3.42 (s, 3H), 3.23 (t, J=7.2 Hz, 2H), 2.87(t, J=7.8 Hz, 2H), 2.12-1.95 (m, 2H).

Example 1.311 Synthesis(2R)—N-tert-butyl-2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]propanamide(Compound 305)

Compound 305 was synthesized similar to compound 101 by replacing4-methoxy-2-(tributylstannyl)pyridine with4-(oxetan-3-yloxy)-2-(trimethylstannyl)pyridine. LCMS (ES) [M+1]⁺ m/z:414. ¹H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J=5.6 Hz, 1H), 8.15 (s,HCOOH), 7.90 (d, J=2.5 Hz, 1H), 7.81 (s, 1H), 7.06 (dd, J=5.7, 2.6 Hz,1H), 5.09 (q, J=7.0 Hz, 1H), 4.16 (t, J=4.9 Hz, 2H), 3.77 (t, J=4.9 Hz,1H), 3.21-3.01 (m, 2H), 3.11 (s, 3H), 2.95-2.72 (m, 2H), 2.13-1.84 (m,2H), 1.32 (d, J=7.0 Hz, 3H), 1.20 (s, 9H).

Example 1.312 Synthesis2-{[2-(5-fluoro-4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(6-methylpyridin-3-yl)acetamide(Compound 306)

Compound 306 was synthesized similar to compound 24 by replacing2-tributylstannylpyridine with5-fluoro-4-methoxy-2-(tributylstannyl)pyridine and by replacingtert-butylamine with 6-methylpyridin-3-amine. LCMS (ES+): [M+H]⁺=423.1.¹H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.97-8.91 (m, 1H), 8.71 (d,J=2.7 Hz, 1H), 8.28 (d, J=8.1 Hz, 1H), 8.03 (s, 1H), 7.62 (d, J=8.6 Hz,1H), 4.82 (s, 2H), 3.90 (s, 3H), 3.60 (s, 3H), 3.50-3.46 (m, 2H),3.09-3.05 (m, 2H), 2.57 (s, 3H), 2.17-2.08 (m, 2H).

Example 1.313 SynthesisN-(3-fluorophenyl)-2-[(2-{4-[(1-hydroxycyclopropyl)methoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 307)

Compound 307 was synthesized similar to compound 252 by replacing1-(2-hydroxyethyl)pyrrolidine with{1-[(tert-butyldimethylsilyl)oxy]cyclopropyl}methanol. LCMS (ES) [M+1]⁺m/z: 464.2. ¹H NMR (300 MHz, DMSO-d₆) δ 10.41 (s, 1H), 8.43 (d, J=5.6Hz, 1H), 7.84 (d, J=2.5 Hz, 1H), 7.55 (ddd, J=11.4, 3.4, 1.9 Hz, 1H),7.45-7.21 (m, 2H), 7.10 (dd, J=5.6, 2.5 Hz, 1H), 6.86 (ddt, J=8.8, 5.5,2.9 Hz, 1H), 4.98 (s, 1H), 4.45 (s, 2H), 3.65 (s, 2H), 3.34 (s, 3H),3.20 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.05-1.96 (m, 2H), 0.93(t, J=6.6 Hz, 2H), 0.86 (d, J=5.0 Hz, 2H).

Example 1.314 Synthesis ofN-(6-cyclopropylpyridin-3-yl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 308)

Compound 308 was synthesized similar to compound 44 by replacingtert-butylamine with 6-cyclopropyl-3-aminopyridine. LCMS (ES) [M+1]⁺m/z: 461. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 10.34 (s, 1H), 8.55 (d, J=2.5Hz, 1H), 8.44 (d, J=5.6 Hz, 1H), 8.14 (HCOOH), 7.88 (dd, J=8.5, 2.6 Hz,1H), 7.78 (d, J=2.5 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.02 (dd, J=5.6,2.6 Hz, 1H), 4.95 (s, 1H), 4.42 (s, 2H), 4.03 (t, J=4.8 Hz, 2H), 3.68(t, J=4.8 Hz, 2H), 3.37 (s, 3H), 3.21 (t, J=7.3 Hz, 2H), 2.84 (t, J=7.9Hz, 2H), 2.06-1.97 (m, 3H), 0.95-0.77 (m, 4H).

Example 1.315 Synthesis of(2R)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)propanamide(Compound 309)

Compound 309 was synthesized similar to compound 251 replacing3-fluoroaniline with 5-amino-2-methoxypyridine. LCMS (ES) [M+1]⁺ m/z:465. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 10.43 (s, 1H), 8.48 (d, J=5.6 Hz,1H), 8.33 (d, J=2.6 Hz, 1H), 7.93-7.83 (m, 2H), 7.07 (dd, J=5.6, 2.6 Hz,1H), 6.76 (d, J=8.9 Hz, 1H), 5.26 (q, J=6.9 Hz, 1H), 4.94 (t, J=5.4 Hz,1H), 4.13 (t, J=4.8 Hz, 2H), 3.79 (s, 3H), 3.74 (q, J=4.9 Hz, 2H), 3.20(s, 3H), 3.24-3.06 (m, 2H), 2.98-2.78 (m, 2H), 2.12-1.92 (m, 2H), 1.46(d, J=7.0 Hz, 3H).

Example 1.316 Synthesis of(2R)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(1-methyl-1H-pyrazol-4-yl)propanamide(Compound 310)

Compound 310 was synthesized similar to compound 251 replacing3-fluoroaniline with 1-methylpyrazol-4-amine. LCMS (ES) [M+1]⁺ m/z: 438.¹H NMR (300 MHz, DMSO-d₆, ppm) δ 10.41 (s, 1H), 8.54 (d, J=5.7 Hz, 1H),7.88 (d, J=2.6 Hz, 1H), 7.84 (s, 1H), 7.38 (s, 1H), 7.12 (dd, J=5.9, 2.7Hz, 1H), 5.26 (q, J=7.1 Hz, 1H), 4.96 (t, J=5.2 Hz, 1H), 4.17 (s, 2H),3.87-3.68 (m, 5H), 3.23-3.09 (m, 5H), 3.03-2.77 (m, 2H), 2.23-1.91 (m,2H), 1.44 (d, J=7.0 Hz, 3H).

Example 1.317 Synthesis of(2R)—N-tert-butyl-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)propanamide(Compound 311)

Compound 311 was synthesized similar to compound 251 replacing3-fluoroaniline with 2-methylpropan-2-amine. LCMS (ES) [M+1]⁺ m/z: 414.¹H NMR (300 MHz, DMSO-d₆, ppm) δ 8.49 (d, J=5.6 Hz, 1H), 8.15 (s,HCOOH), 7.90 (d, J=2.5 Hz, 1H), 7.81 (s, 1H), 7.06 (dd, J=5.7, 2.6 Hz,1H), 5.09 (q, J=7.0 Hz, 1H), 4.16 (t, J=4.9 Hz, 2H), 3.77 (t, J=4.9 Hz,1H), 3.21-3.01 (m, 2H), 3.11 (s, 3H), 2.95-2.72 (m, 2H), 2.13-1.84 (m,2H), 1.32 (d, J=7.0 Hz, 3H), 1.20 (s, 9H).

Example 1.318 Synthesis of(2R)—N-(6-methoxypyridin-3-yl)-2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]propanamide(Compound 312)

Compound 312 was synthesized similar to compound 245 replacingN-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamidewith(2R)-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(6-methoxypyridin-3-yl)propanamide.LCMS (ES) [M+1]⁺ m/z: 477. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 10.35 (s,1H), 8.50 (d, J=5.6 Hz, 1H), 8.33 (d, J=2.6 Hz, 1H), 8.15 (s, HCOOH),7.89 (dd, J=8.9, 2.7 Hz, 1H), 7.73 (d, J=2.6 Hz, 1H), 6.91 (dd, J=5.6,2.6 Hz, 1H), 6.75 (d, J=8.9 Hz, 1H), 5.50-5.42 (m, 1H), 5.20 (q, J=7.0Hz, 1H), 4.97 (td, J=6.7, 4.1 Hz, 2H), 4.64-4.53 (m, 2H), 3.79 (s, 3H),3.33-3.05 (m, 5H), 2.96-2.73 (m, 2H), 2.18-1.86 (m, 2H), 1.47 (d, J=7.0Hz, 3H).

Example 1.319 Synthesis ofN-(4-fluorophenyl)-2-[methyl(2-{1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 313)

Compound 313 was synthesized similar to compound 24 by replacing2-tributylstannylpyridine with1-methyl-5-(tributylstannyl)-1H-pyrazolo[3,4-c]pyridine and by replacingtert-butylamine with 4-fluoroaniline. LCMS (ES+): [M+H]⁺=432.1. ¹H NMR(400 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.37 (s, 1H), 8.95 (s, 1H), 8.26 (s,1H), 7.71 (dd, J=8.9, 5.0 Hz, 2H), 7.16 (dd, J=8.9 Hz, 2H), 4.69 (s,2H), 4.27 (s, 3H), 3.58 (s, 3H), 3.39-3.38 (m, 2H), 3.11-3.04 (m, 2H),2.17-2.06 (m, 2H).

Example 1.320 Synthesis ofN-(4-fluorophenyl)-2-[methyl(2-{2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 314)

Compound 314 was synthesized similar to compound 24 by replacing2-tributylstannylpyridine with2-methyl-5-(tributylstannyl)-1H-pyrazolo[3,4-c]pyridine and by replacingtert-butylamine with 4-fluoroaniline. LCMS (ES+): [M+H]⁺=432.1. ¹H NMR(400 MHz, DMSO-d6) δ 10.77-10.64 (m, 1H), 9.30 (s, 1H), 8.93 (d, J=1.3Hz, 1H), 8.69 (s, 1H), 7.74-7.65 (m, 2H), 7.15 (dd, J=8.9 Hz, 2H), 4.65(s, 2H), 4.33 (s, 3H), 3.53 (s, 3H), 3.04-2.99 (m, 2H), 2.13-2.05 (m,2H).

Example 1.321 Synthesis of2-({2-[4-({[1-(3-fluorophenyl)-1H-1,2,4-triazol-5-yl]methyl}(methyl)amino)-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]pyridin-4-yl}oxy)ethan-1-ol(Compound 315)

Step 1

Into a 50 mL round-bottom flask were added tert-butylN-(carbamoylmethyl)carbamate (2.0 g, 11.48 mmol, 1.00 equiv), THF (20mL) and DMF-DMA (2.74 g, 22.99 mmol, 2.00 equiv) at room temperature.The resulting mixture was stirred for 2 h at 60° C. The resultingmixture was cooled to room temperature and concentrated under reducedpressure. This resulted in 2.5 g of tert-butyl(2-(((dimethylamino)methylene)amino)-2-oxoethyl)carbamate as a yellowoil. The crude product was used to the next step directly withoutfurther purification. LCMS (ES) [M+1]⁺ m/z: 230.

Step 2

Into a 100 mL round-bottom flask were added tert-butyl(2-(((dimethylamino)methylene)amino)-2-oxoethyl)carbamate (2.5 g, 10.90mmol, 1.00 equiv), HOAc (30 mL) and (3-fluorophenyl)hydrazinehydrochloride (1.77 g, 10.90 mmol, 1.00 equiv) at room temperature. Theresulting mixture was stirred for 1 h at 60° C. The resulting mixturewas cooled to room temperature and concentrated under reduced pressure.The residue was purified by silica gel column chromatography, elutedwith PE/EA (5:1) to afford tert-butyl((1-(3-fluorophenyl)-1H-1,2,4-triazol-5-yl)methyl)carbamate (1.5 g, 45%in total from step one) as a brown solid. LCMS (ES) [M+1]⁺ m/z: 293.

Step 3

Into a 100 mL 3-necked round-bottom flask were added tert-butyl((1-(3-fluorophenyl)-1H-1,2,4-triazol-5-yl)methyl)carbamate (1.5 g, 5.13mmol, 1.00 equiv) and DMF (30 mL). To the above mixture was added NaH(60% in mineral oil) (190 mg, 7.92 mmol, 1.50 equiv) in portions at 0°C. The resulting mixture was stirred for additional 30 min at the sametemperature. To the above mixture was added CH₃I (1.75 g, 12.31 mmol,2.4 equiv) dropwise at 0° C. The resulting mixture was stirred foradditional 1 h at room temperature. The reaction was quenched by theaddition of water (30 mL), extracted with EtOAc (50 mL*2). The combinedorganic phases were washed with brine (30 mL*3), dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EA (3:1) to afford tert-butyl((1-(3-fluorophenyl)-1H-1,2,4-triazol-5-yl)methyl)(methyl)carbamate (1.5g, 95%) as a yellow oil. LCMS (ES) [M+1]⁺ m/z: 307.

Step 4

Into a 100 mL round-bottom flask were added tert-butyl((1-(3-fluorophenyl)-1H-1,2,4-triazol-5-yl)methyl)(methyl)carbamate (1.5g, 4.90 mmol, 1.00 equiv), DCM (30 mL) and HCl (g) (2 M in Et₂O) (30 mL)at room temperature. The resulting mixture was stirred for 6 h at roomtemperature. The resulting mixture was concentrated under vacuum. Thisresulted in 1.5 g crude of1-(1-(3-fluorophenyl)-1H-1,2,4-triazol-5-yl)-N-methylmethanaminehydrochloride as a yellow solid used in the next step directly withoutfurther purification. LCMS (ES) [M−HCl+1]⁺ m/z: 207.

Step 5

Into a 100 mL round-bottom flask were added2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (777 mg, 4.11 mmol, 1.00equiv), NMP (30 mL),1-(1-(3-fluorophenyl)-1H-1,2,4-triazol-5-yl)-N-methylmethanaminehydrochloride (1.56 g, 6.17 mmol, 1.5 equiv) and DIEA (1.6 g, 12.38mmol, 3.00 equiv) at room temperature. The resulting mixture was stirredfor 16 h at 60° C. The reaction was cooled to room temperature andquenched by the addition of water (30 mL), extracted with EtOAc (50mL*2). The combined organic phases were washed with brine (30 mL),concentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with PE/EA (1:1) to afford2-chloro-N-((1-(3-fluorophenyl)-1H-1,2,4-triazol-5-yl)methyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(1.0 g, 68%) as a yellow oil. LCMS (ES) [M+1]⁺ m/z: 359.

Step 6

Into a 40 mL vial were added2-chloro-N-((1-(3-fluorophenyl)-1H-1,2,4-triazol-5-yl)methyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(650 mg, 1.81 mmol, 0.70 equiv), toluene (30 mL),4-[2-(oxan-2-yloxy)ethoxy]-2-(trimethylstannyl)pyridine (1 g, 2.59 mmol,1.00 equiv) and Pd(PPh₃)₄ (300 mg, 0.26 mmol, 0.10 equiv) at roomtemperature. The resulting mixture was stirred for 12 h at 100° C. undernitrogen atmosphere. The reaction mixture was cooled to roomtemperature, concentrated under reduced pressure to remove the solvent,the residue was purified by silica gel column chromatography, elutedwith CH₂Cl₂/MeOH (10:1) to affordN-((1-(3-fluorophenyl)-1H-1,2,4-triazol-5-yl)methyl)-N-methyl-2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(300 mg, 21%) as a yellow oil. LCMS (ES) [M+1]⁺ m/z: 546.

Step 7

Into a 20 mL vial were addedN-((1-(3-fluorophenyl)-1H-1,2,4-triazol-5-yl)methyl)-N-methyl-2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(300 mg, 0.55 mmol, 1.00 equiv), MeOH (5 mL) and TsOH (95 mg, 0.55 mmol,1.00 equiv) at room temperature. The resulting solution was stirred for1 h at room temperature. The reaction solution was purified by Prep-HPLCwith the following conditions: Sunfire Prep C18 OBD Column, 50*250 mm, 5μm, 10 nm, mobile phase, water (0.1% FA) and CH₃CN (5% Phase B up to 23%in 12 min), Detector, UV 254 nm. The fraction of the target was freezingdried, this resulted in 158.4 mg (57%) of2-((2-(4-(((1-(3-fluorophenyl)-1H-1,2,4-triazol-5-yl)methyl)(methyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyridin-4-yl)oxy)ethan-1-olformate as a brown semi-solid. LCMS [M+H]⁺: 462. ¹H NMR (300 MHz,DMSO-d₆) δ 8.41 (d, J=5.6 Hz, 1H), 8.07 (s, 1H), 7.66 (dt, J=9.0, 1.8Hz, 1H), 7.66-7.47 (m, 3H), 7.39-7.26 (m, 1H), 7.01 (dd, J=5.6, 2.6 Hz,1H), 5.15 (s, 2H), 4.11 (t, J=4.8 Hz, 2H), 3.77 (t, J=4.8 Hz, 2H), 3.29(s, 3H), 3.06 (t, J=7.3 Hz, 2H), 2.79 (t, J=7.8 Hz, 2H), 2.00-1.90 (p,J=7.6 Hz, 2H).

Example 1.322 Synthesis of(2R)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methylpyridin-3-yl)propanamide(Compound 316)

Compound 316 was synthesized similar to compound 251 by replacing3-fluoroaniline with 6-methylpyridin-3-am. LCMS (ES) [M+1]⁺ m/z: 449. ¹HNMR (300 MHz, DMSO-d₆, ppm) δ 10.58 (s, 1H), 8.61 (d, J=2.6 Hz, 1H),8.47 (d, J=5.6 Hz, 1H), 8.16 (s, HCOOH), 7.91 (dd, J=8.4, 2.6 Hz, 1H),7.86 (d, J=2.5 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.06 (dd, J=5.6, 2.6 Hz,1H), 5.26 (q, J=6.9 Hz, 1H), 4.12 (t, J=4.8 Hz, 2H), 3.75 (t, J=4.7 Hz,2H), 3.19 (s, 3H), 3.26-3.00 (m, 2H), 2.96-2.70 (m, 2H), 2.37 (s, 3H),2.17-1.84 (m, 2H), 1.46 (d, J=7.0 Hz, 3H).

Example 1.323 Synthesis ofN-tert-butyl-2-[methyl(2-{4-[(3S)-oxolan-3-yloxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 317)

Compound 317 was synthesized similar to compound 174 by replacing2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with(3S)-oxolan-3-ol. LCMS (ES) [M+1]⁺ m/z: 426. ¹H NMR (300 MHz, DMSO-d₆,ppm) δ 8.48 (d, J=5.6 Hz, 1H), 7.84 (d, J=2.6 Hz, 1H), 7.69 (s, 1H),7.04 (dd, J=5.7, 2.6 Hz, 1H), 5.22 (t, J=3.2 Hz, 1H), 4.11 (s, 2H), 3.95(dd, J=10.3, 4.5 Hz, 1H), 3.93-3.73 (m, 3H), 3.27 (s, 3H), 3.15 (t,J=7.3 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.39-2.21 (m, 1H), 2.04-1.97 (m,3H), 1.25 (s, 9H).

Example 1.324 Synthesis ofN-tert-butyl-2-[methyl(2-{4-[(3R)-oxolan-3-yloxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 318)

Compound 318 was synthesized similar to compound 174 by replacing2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with(3R)-oxolan-3-ol. LCMS (ES) [M+1]⁺ m/z: 426. ¹H NMR (300 MHz, DMSO-d₆,ppm) δ 8.48 (d, J=5.6 Hz, 1H), 7.84 (d, J=2.6 Hz, 1H), 7.69 (s, 1H),7.04 (dd, J=5.7, 2.6 Hz, 1H), 5.22 (t, J=3.2 Hz, 1H), 4.11 (s, 2H), 3.95(dd, J=10.3, 4.5 Hz, 1H), 3.93-3.73 (m, 3H), 3.27 (s, 3H), 3.15 (t,J=7.3 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.39-2.21 (m, 1H), 2.04-1.97 (m,3H), 1.25 (s, 9H).

Example 1.325 Synthesis of2-({2-[4-({[4-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl]methyl}(methyl)amino)-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]pyridin-4-yl}oxy)ethan-1-ol(Compound 319)

Step 1

Into a 250-mL round-bottom flask, was placed1-fluoro-3-isothiocyanatobenzene (5 g, 32.643 mmol, 1.00 equiv),2-methoxyacetohydrazide (3.98 g, 38.229 mmol, 1.17 equiv) and EtOH(60.00 mL). The resulting solution was stirred for 1 hr at 80 degrees C.The precipitate was collected and recrystallized from H₂O. The solid andNaOH (130.57 mL, 261.144 mmol, 8.00 equiv) was placed into a 250 mLround-bottom flask. The resulting solution was allowed to react, withstirring, for an additional 1 hr at 100 degrees C. The resultingsolution was transferred to a beaker, neutralized to 6 with HCl (2mol/L), applied to suction filtration, washed with water. This resultedin 6 g (76.9%) of4-(3-fluorophenyl)-5-(methoxymethyl)-2H-1,2,4-triazole-3-thione as awhite solid. LCMS (ES) [M+1]⁺ m/z: 240.

Step 2

A solution of starting4-(3-fluorophenyl)-5-(methoxymethyl)-2H-1,2,4-triazole-3-thione (5.5 g,22.987 mmol, 1.00 equiv) in CH₂Cl₂ (40 mL) was cooled to 0° C., and a30% aqueous solution of H₂O₂ (1.18 mL, 50.649 mmol, 2.20 equiv) in AcOH(27 mL) was added in portions under cooling and stirring. Then the icebath was removed, and the stirring was continued at ambient temperaturefor 3 h. The reaction mixture was alkalized under cooling with NaOH topH 10. The organic layer was separated, and the aqueous one was washedwith CH₂Cl₂ (2×100 mL). The combined extracts were dried with Na₂SO₄ andevaporated. The residue was purified by column chromatography (DCM/MeOH,100:0˜70:30). This resulted in 3.2 g (67.18%) of4-(3-fluorophenyl)-3-(methoxymethyl)-1,2,4-triazole as a off-whitesolid. LCMS (ES) [M+1]⁺ m/z: 208.

Step 3

Into a 250-mL round-bottom flask, was placed4-(3-fluorophenyl)-3-(methoxymethyl)-1,2,4-triazole (3.00 g, 14.478mmol, 1.00 equiv), AlCl₃ (19.31 g, 144.782 mmol, 10 equiv), AcCN (100.00mL). The resulting solution was stirred for 16 hr at 80° C. The reactionmixture was cooled, and the crude product was purified byFlash-Prep-HPLC with the following conditions (IntelFlash-1): Column,C18 silica gel; mobile phase, H₂O(FA)/ACN=10:1 increasing toH₂O(FA)/ACN=5:1 within 15 min. This resulted in 1.2 g (42.90%) of[4-(3-fluorophenyl)-1,2,4-triazol-3-yl]methanol as a yellow solid. LCMS(ES) [M+1]⁺ m/z: 194.

Step 4

Into a 100-mL round-bottom flask were placed[4-(3-fluorophenyl)-1,2,4-triazol-3-yl]methanol (1.20 g, 6.212 mmol,1.00 equiv), SOCl₂ (1.11 g, 9.330 mmol, 1.50 equiv), DCM (30.00 mL). Theresulting solution was stirred for 6 hr at room temperature. Theresulting mixture was concentrated under vacuum. The resulting solutionwas extracted with 3×30 mL of dichloromethane and the organic layerscombined and dried over anhydrous sodium sulfate and concentrated. Thisresulted in 1.28 g (97.37%) of3-(chloromethyl)-4-(3-fluorophenyl)-1,2,4-triazole as colorless oil.LCMS (ES) [M+1]⁺ m/z: 212.

Step 5

Into a 100-mL round-bottom flask were placed3-(chloromethyl)-4-(3-fluorophenyl)-1,2,4-triazole (1.20 g, 5.671 mmol,1.00 equiv), Methylamine in ethanol (30 wt. % 0.86 g, 8.372 mmol, 1.48equiv), EtOH (30.00 mL). The resulting solution was stirred for 4 hr at60° C. The resulting solution was extracted with 3×30 mL ofdichloromethane and the organic layers combined and dried over anhydroussodium sulfate and concentrated. This resulted in 1.0 g (85.51%) of[[4-(3-fluorophenyl)-1,2,4-triazol-3-yl]methyl](methyl)amine as a whitesolid. LCMS (ES) [M+1]⁺ m/z: 207.

Step 6

Into a 100 mL round-bottom flask were placed[[4-(3-fluorophenyl)-1,2,4-triazol-3-yl]methyl](methyl)amine (1.00 g,4.849 mmol, 1.00 equiv), 2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine(1.10 g, 5.819 mmol, 1.20 equiv), DIEA (1.25 g, 9.698 mmol, 2 equiv),MeOH (20.00 mL). The resulting solution was stirred for 8 hr at roomtemperature. The resulting solution was extracted with 3×30 mL ofdichloromethane and the organic layers combined, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (3:1). Thisresulted in 1 g (57.47%) of2-chloro-N-[[4-(3-fluorophenyl)-1,2,4-triazol-3-yl]methyl]-N-methyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-amineas a white solid. LCMS (ES) [M+1]⁺ m/z: 359.

Step 6

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed2-chloro-N-[[4-(3-fluorophenyl)-1,2,4-triazol-3-yl]methyl]-N-methyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(700.00 mg, 1.951 mmol, 1.00 equiv),4-fluoro-2-(tributylstannyl)pyridine (903.99 mg, 2.341 mmol, 1.20equiv), Pd(dppf)Cl₂ (285.49 mg, 0.390 mmol, 0.2 equiv), DMF (30.00 mL).The resulting solution was stirred for 16 hr at 120° C. The reactionmixture was cooled. The residue was applied onto a silica gel columnwith dichloromethane/methanol (10:1). This resulted in 230 mg (28.11%)ofN-[[4-(3-fluorophenyl)-1,2,4-triazol-3-yl]methyl]-2-(4-fluoropyridin-2-yl)-N-methyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-amineas brown oil. LCMS (ES) [M+1]⁺ m/z: 420.

Step 7

Into a 100-mL round-bottom flask, was placedN-[[4-(3-fluorophenyl)-1,2,4-triazol-3-yl]methyl]-2-(4-fluoropyridin-2-yl)-N-methyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(200.00 mg, 0.477 mmol, 1.00 equiv), NaH (57.21 mg, 2.384 mmol, 5equiv), DMSO (10.00 mL). The resulting solution was stirred for 30 minat 0° C. and ethylene glycol (147.98 mg, 2.384 mmol, 5.00 equiv) wasadded, the solution was stirred for 2 hr at room temperature. Theresulting solution was extracted with 3×30 mL of dichloromethane and theorganic layers combined, dried over anhydrous sodium sulfate andconcentrated. The residue was purified by prep-HPLC with the followingconditions: Column: Sunfire Prep C18 OBD Column, 50*250 mm, 5 μm 10 nm;Mobile Phase A: Water (0.1% FA), Mobile Phase B: AcCN; Flow rate: 90mL/min; Gradient: 5% B to 35% B in 15 min, 35% B; Wave Length: 220 nm.This resulted in 63.9 mg (29.04%) of2-([2-[4-([[4-(3-fluorophenyl)-1,2,4-triazol-3-yl]methyl](methyl)amino)-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]pyridin-4-yl]oxy)ethanol2-([2-[4-([[4-(3-fluorophenyl)-1,2,4-triazol-3-yl]methyl](methyl)amino)-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]pyridin-4-yl]oxy)ethanolformate a brown solid. LCMS (ES) [M+1]⁺ m/z: 462. ¹H NMR (300 MHz,DMSO-d₆) δ 8.72 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 7.67 (d, J=2.6 Hz, 1H),7.63-7.53 (m, 1H), 7.48-7.33 (m, 2H), 7.25-7.19 (m, 1H), 7.02 (dd,J=5.7, 2.6 Hz, 1H), 5.13 (s, 2H), 4.16 (t, J=4.9 Hz, 2H), 3.78 (t, J=4.8Hz, 2H), 3.14 (s, 3H), 2.99 (t, J=7.3 Hz, 2H), 2.77 (t, J=7.8 Hz, 2H),1.98-1.88 (m, 2H).

Example 1.326 Synthesis of(3S)-1-(3-fluorophenyl)-3-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)piperidin-2-one(Compound 320)

Step 1

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tert-butylN-(2-oxopiperidin-3-yl)carbamate (10.00 g, 46.67 mmol, 1.00 equiv),methyl[(methylamino)methyl]amine (0.69 g, 9.31 mmol, 0.20 equiv),1-fluoro-3-iodobenzene (12.43 g, 56.01 mmol, 1.20 equiv), dioxane(100.00 mL), K₃PO₄ (19.81 g, 93.34 mmol, 2.00 equiv), CuI (0.89 g, 4.67mmol, 0.10 equiv). The resulting solution was stirred for overnight at110° C. The reaction mixture was cooled to room temperature. The solidswere filtered out. The resulting mixture was concentrated. The residuewas applied onto a silica gel column with THF/PE (15%). This resulted in8 g (55.59%) of tert-butylN-[1-(3-fluorophenyl)-2-oxopiperidin-3-yl]carbamate as yellow solid.LCMS (ES) [M+1]⁺ m/z: 309.

Step 2

Into a 250-mL 3-necked round-bottom flask, was placed tert-butylN-[1-(3-fluorophenyl)-2-oxopiperidin-3-yl]carbamate (8.00 g, 25.94 mmol,1.00 equiv), DMF (100.00 mL). This was followed by the addition of NaH(0.93 g, 38.75 mmol, 1.49 equiv), in portions at 0° C. To this was addedMeI (4.42 g, 31.13 mmol, 1.20 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred for 3 h at room temperature. The reactionwas then quenched by the addition of 50 mL of water/ice. The resultingsolution was extracted with 3×100 mL of ethyl acetate and the organiclayers combined and dried over anhydrous sodium sulfate andconcentrated. The residue was applied onto a silica gel column withTHF/PE (20%). This resulted in 6.5 g (77.71%) of tert-butylN-[1-(3-fluorophenyl)-2-oxopiperidin-3-yl]-N-methylcarbamate ascolorless oil. LCMS (ES) [M+1]⁺ m/z: 323.

Step 3

Into a 250-mL round-bottom flask, was placed tert-butylN-[1-(3-fluorophenyl)-2-oxopiperidin-3-yl]-N-methylcarbamate (6.50 g,20.16 mmol, 1.00 equiv), DCM (20.00 mL). This was followed by theaddition of HCl (gas) in 1,4-dioxane (10.08 mL, 40.32 mmol, 2.00 equiv)dropwise with stirring at 0° C. The resulting solution was stirred for 3h at room temperature. The solids were collected by filtration. Thisresulted in 5 g (95.85%) of1-(3-fluorophenyl)-3-(methylamino)piperidin-2-one hydrochloride as awhite solid. LCMS (ES) [M−HCl+1]+ m/z: 223.

Step 4

Into a 100-mL round-bottom flask, was placed2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (2.00 g, 10.58 mmol, 1.00equiv), 1-(3-fluorophenyl)-3-(methylamino)piperidin-2-one hydrochloride(2.74 g, 10.58 mmol, 1.00 equiv), NMP (20.00 mL), DIEA (4.10 g, 31.74mmol, 3.00 equiv). The resulting solution was stirred for 5 h at 60° C.The reaction mixture was cooled to room temperature. The crude product(5 g) was purified by Prep-HPLC with the following conditions: Column,XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um; mobile phase, Water(0.1% NH₃·H₂O) and CAN (30% Phase B up to 80% in 11 min); Detector, 254.This resulted in 2 g (50.43%) of3-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-1-(3-fluorophenyl)piperidin-2-oneas yellow solid. LCMS (ES) [M+1]⁺ m/z: 375.

Step 5

Into a 40-mL vial purged and maintained with an inert atmosphere ofnitrogen, was placed3-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-1-(3-fluorophenyl)piperidin-2-one(2.00 g, 5.34 mmol, 1.00 equiv), DMF (20.00 mL),4-fluoro-2-(tributylstannyl)pyridine (2.68 g, 6.94 mmol, 1.30 equiv),Pd(PPh₃)₄ (0.62 g, 0.54 mmol, 0.10 equiv). The resulting solution wasstirred for overnight at 120° C. The reaction mixture was cooled to roomtemperature. The resulting mixture was concentrated. The residue wasapplied onto a silica gel column with THF/PE (60%). This resulted in 1 g(43.04%) of1-(3-fluorophenyl)-3-[[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]piperidin-2-oneas yellow oil. LCMS (ES) [M+1]⁺ m/z: 436.

Step 6

Into a 100-mL 3-necked round-bottom flask, was placed2-(oxan-2-yloxy)ethanol (0.30 g, 2.05 mmol, 1.00 equiv), DMF (10.00 mL).This was followed by the addition of NaH (0.10 g, 4.17 mmol, 2.03equiv), in portions at 0° C. To this was added1-(3-fluorophenyl)-3-[[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]piperidin-2-one(0.98 g, 2.26 mmol, 1.10 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred for 3 h at room temperature. The reactionwas then quenched by the addition of 10 mL of water/ice. The resultingsolution was extracted with 3×20 mL of ethyl acetate and the organiclayers combined and dried over anhydrous sodium sulfate andconcentrated. The residue was applied onto a silica gel column withTHF/PE (50%). This resulted in 0.7 g (60.73%) of1-(3-fluorophenyl)-3-[methyl(2-[4-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]piperidin-2-one as a yellow oil. LCMS(ES) [M+1]⁺ m/z: 562.

Step 7

Into a 40-mL vial, was placed1-(3-fluorophenyl)-3-[methyl(2-[4-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]piperidin-2-one(700.00 mg, 1.25 mmol, 1.00 equiv), MeOH (10.00 mL), PTSA (42.92 mg,0.25 mmol, 0.20 equiv). The resulting solution was stirred for 3 h atroom temperature. The crude product (0.8 g) was purified by Prep-HPLCwith the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150 mm, 5 um; mobile phase, Water (0.1% NH₃·H₂O) and CAN (30% PhaseB up to 70% in 11 min); Detector, 254. This resulted in 400 mg (67.21%)of1-(3-fluorophenyl)-3-([2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)piperidin-2-oneas white solid. LCMS (ES) [M+1]⁺ m/z: 478.

Step 8

Into a 100-mL round-bottom flask, was placed1-(3-fluorophenyl)-3-([2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)piperidin-2-one(400.00 mg, 0.84 mmol, 1.00 equiv), DCM (6.00 mL), imidazole (85.54 mg,1.26 mmol, 1.50 equiv). This was followed by the addition oft-butyldimethylchlorosilane (151.50 mg, 1.01 mmol, 1.20 equiv), inportions at 0° C. The resulting solution was stirred for 5 h at roomtemperature. The resulting mixture was concentrated. The crude product(500 mg) was purified by Prep-CHIRAL-HPLC with the following conditions:Column, YMC Cellulose-SC, 250*21.5 mm, 5 μm; mobile phase, Acetonitrileand Ethanol (0.2% DEA) (70% in 10 min); Detector, 254. This resulted in220 mg (44.38%) of (3S)-3-[[2-(4-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-1-(3-fluorophenyl)piperidin-2-oneas white solid. LCMS (ES) [M+1]⁺ m/z: 592.

Step 9

Into a 40-mL vial, was placed(3S)-3-[[2-(4-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-1-(3-fluorophenyl)piperidin-2-one(220.00 mg, 0.37 mmol, 1.00 equiv), THF (6.00 mL), Et₃N·3HF (299.64 mg,1.86 mmol, 5.00 equiv). The resulting solution was stirred for overnightat room temperature. The crude product (0.3 g) was purified by Prep-HPLCwith the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150 mm, 5 um; mobile phase, Water (0.1% FA) and CAN (5% Phase B upto 40% in 11 min); Detector, 254. This resulted in 130 mg (73.23%) of(3S)-1-(3-fluorophenyl)-3-([2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)piperidin-2-oneas white solid. Chiral analytical HPLC condition: Column, (R,R)-WHELK-O150*4.6 mm, 3.5 um; mobile phase, n-hexane and Ethanol (0.2% DEA) (50% in6 min); Detector, 254, Retention time: 3.233 min. LCMS (ES, m/z):[M+H]⁺: 478. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 8.45 (d, J=5.6 Hz, 1H),7.76 (d, J=2.6 Hz, 1H), 7.34-7.23 (m, 1H), 7.12-6.93 (m, 4H), 4.92 (d,J=6.3 Hz, 1H), 4.61 (s, 1H), 4.14 (t, J=4.9 Hz, 3H), 3.75 (d, J=5.1 Hz,2H), 3.56 (d, J=11.6 Hz, 1H), 3.30 (s, 3H), 3.21 (q, J=6.8 Hz, 2H), 2.83(t, J=7.9 Hz, 2H), 2.55 (s, 1H), 2.10-1.98 (m, 5H).

Example 1.327 Synthesis of(3R)-1-(3-fluorophenyl)-3-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)piperidin-2-one(Compound 321)

Step 1

Into a 100-mL round-bottom flask, was placed1-(3-fluorophenyl)-3-([2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)piperidin-2-one(400.00 mg, 0.84 mmol, 1.00 equiv), DCM (6.00 mL), imidazole (85.54 mg,1.26 mmol, 1.50 equiv). This was followed by the addition oft-butyldimethylchlorosilane (151.50 mg, 1.01 mmol, 1.20 equiv), inportions at 0° C. The resulting solution was stirred for 5 h at roomtemperature. The resulting mixture was concentrated. The crude product(500 mg) was purified by Prep-CHIRAL-HPLC with the following conditions:Column, YMC Cellulose-SC, 250*21.5 mm, 5 μm; mobile phase, Acetonitrileand Ethanol (0.2% DEA) (70% in 10 min); Detector, 254. This resulted in220 mg (44.38%) of(3R)-3-[[2-(4-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-1-(3-fluorophenyl)piperidin-2-oneas a white solid. LCMS (ES) [M+1]⁺ m/z: 592.

Step 2

Into a 40-mL vial, was placed(3S)-3-[[2-(4-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-1-(3-fluorophenyl)piperidin-2-one(220.00 mg, 0.37 mmol, 1.00 equiv), THF (6.00 mL), Et₃N·3HF (299.64 mg,1.86 mmol, 5.00 equiv). The resulting solution was stirred for overnightat room temperature. The crude product (0.3 g) was purified by Prep-HPLCwith the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150 mm, 5 um; mobile phase, Water (0.1% FA) and CAN (5% Phase B upto 40% in 11 min); Detector, 254. This resulted in 109 mg (61.40%) of(3R)-1-(3-fluorophenyl)-3-([2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)piperidin-2-oneas white solid. Chiral analytical HPLC condition: Column, (R,R)-WHELK-O150*4.6 mm, 3.5 um; mobile phase, n-hexane and Ethanol (0.2% DEA) (50% in6 min); Detector, 254, Retention time: 2.274 min. LCMS (ES, m/z):[M+H]⁺: 478. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 8.45 (d, J=5.7 Hz, 1H),7.76 (d, J=2.6 Hz, 1H), 7.30 (q, J=8.1, 7.3 Hz, 1H), 7.10-6.94 (m, 4H),4.94 (s, 1H), 4.63 (s, 1H), 4.15 (t, J=4.9 Hz, 3H), 3.75 (d, J=4.7 Hz,2H), 3.56 (d, J=11.4 Hz, 1H), 3.31 (s, 3H), 3.19 (dt, J=11.9, 7.8 Hz,2H), 2.83 (t, J=7.9 Hz, 2H), 2.55 (s, 1H), 2.10-1.98 (m, 5H).

Example 1.328 Synthesis ofN-tert-butyl-N-methyl-2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide(Compound 322)

Compound 322 was synthesized similar to compound 253 by replacing5-amino-2-methoxypyridine with tert-butyl(methyl)amine. LCMS (ES) [M+1]⁺m/z: 426. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 8.41 (d, J=5.7 Hz, 1H), 7.59(d, J=2.6 Hz, 1H), 6.79 (dd, J=5.8, 2.6 Hz, 1H), 5.41-5.31 (m, 1H), 4.97(t, J=6.7 Hz, 2H), 4.55 (dd, J=7.7, 4.5 Hz, 2H), 3.20 (s, 3H), 3.07 (t,J=7.5 Hz, 2H), 2.90 (s, 3H), 2.77 (t, J=7.8 Hz, 2H), 1.99-1.88 (m, 2H),1.25 (s, 9H).

Example 1.329 Synthesis of2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]-1-(piperidin-1-yl)ethan-1-one(Compound 323)

Compound 323 was synthesized similar to compound 253 by replacing5-amino-2-methoxypyridine with piperidine. LCMS (ES) [M+1]⁺ m/z: 424. ¹HNMR (300 MHz, DMSO-d₆, ppm) δ 8.48 (d, J=5.6 Hz, 1H), 7.65 (d, J=2.6 Hz,1H), 6.86 (dd, J=5.6, 2.6 Hz, 1H), 5.49-5.43 (m, 1H), 4.97 (t, J=6.7 Hz,2H), 4.58 (dd, J=7.5, 4.9 Hz, 2H), 4.51 (s, 2H), 3.50-3.38 (m, 4H), 3.25(s, 3H), 3.14 (t, J=7.4 Hz, 2H), 2.81 (t, J=7.9 Hz, 2H), 2.04-1.96 (m,2H), 1.69-1.57 (m, 4H), 1.51-1.40 (m, 2H).

Example 1.330 Synthesis of2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]-N-(6-methylpyridin-3-yl)acetamide(Compound 324)

Compound 324 was synthesized similar to compound 253 by replacing5-amino-2-methoxypyridine with 6-methylpyridin-3-amine. LCMS (ES) [M+1]⁺m/z: 447. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 10.35 (s, 1H), 8.62 (d, J=2.5Hz, 1H), 8.45 (d, J=5.6 Hz, 1H), 7.92 (dd, J=8.4, 2.6 Hz, 1H), 7.63 (d,J=2.5 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.84 (dd, J=5.6, 2.6 Hz, 1H),5.36-5.33 (m, 1H), 4.95-4.85 (m, 2H), 4.52 (dd, J=7.6, 4.8 Hz, 2H), 4.42(s, 2H), 3.37 (s, 3H), 3.21 (t, J=7.4 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H),2.40 (s, 3H), 2.04-1.99 (m, 2H).

Example 1.331 Synthesis ofN-(4-chlorophenyl)-2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide(Compound 325)

Compound 325 was synthesized similar to compound 253 by replacing5-amino-2-methoxypyridine with 4-chloroaniline. LCMS (ES) [M+1]⁺ m/z:466. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 10.36 (s, 1H), 8.46 (d, J=5.6 Hz,1H), 7.65 (d, J=8.8 Hz, 2H), 7.62 (d, J=2.6 Hz, 1H), 7.35 (d, J=8.8 Hz,2H), 6.85 (dd, J=5.6, 2.6 Hz, 1H), 5.41-5.28 (m, 1H), 4.90 (t, J=6.7 Hz,2H), 4.51 (dd, J=7.5, 4.7 Hz, 2H), 4.42 (s, 2H), 3.21 (t, J=7.3 Hz, 2H),2.83 (t, J=7.8 Hz, 2H), 2.08-1.93 (m, 2H).

Example 1.332 Synthesis of2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]-N-(4-methylphenyl)acetamide(Compound 326)

Compound 326 was synthesized similar to compound 253 by replacing5-amino-2-methoxypyridine with 4-methylaniline. LCMS (ES) [M+1]⁺ m/z:446. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 10.11 (s, 1H), 8.46 (d, J=5.7 Hz,1H), 7.64 (t, J=1.9 Hz, 1H), 7.49 (d, J=8.0 Hz, 2H), 7.10 (d, J=8.0 Hz,2H), 6.91-6.82 (m, 1H), 5.38-5.29 (m, 1H), 4.90 (t, J=6.7 Hz, 2H), 4.51(dd, J=7.4, 4.7 Hz, 2H), 4.41 (s, 2H), 3.36 (s, 3H), 3.21 (t, J=7.4 Hz,2H), 2.83 (t, J=7.9 Hz, 2H), 2.24 (s, 3H), 2.11-1.93 (m, 2H).

Example 1.333 Synthesis ofN-(4-methoxyphenyl)-2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide(Compound 327)

Compound 327 was synthesized similar to compound 253 by replacing5-amino-2-methoxypyridine with p-anisidine. LCMS (ES) [M+1]⁺ m/z: 462.¹H NMR (300 MHz, DMSO-d₆, ppm) δ 10.05 (s, 1H), 8.46 (d, J=5.6 Hz, 1H),7.64 (d, J=2.5 Hz, 1H), 7.57-7.46 (m, 2H), 6.93-6.82 (m, 3H), 5.38-5.31(m, 1H), 4.96-4.85 (m, 2H), 4.52 (dd, J=7.5, 4.7 Hz, 2H), 4.38 (s, 2H),3.71 (s, 3H), 3.31 (s, 3H), 3.20 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.8 Hz,2H), 2.11-1.93 (m, 2H).

Example 1.334 Synthesis ofN-tert-butyl-2-[methyl(2-{[1,3]thiazolo[5,4-c]pyridin-6-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 328)

Compound 328 was synthesized similar to compound 245 by replacing2-chloro-4-(oxetan-3-yloxy)pyridine with6-chloro-[1,3]thiazolo[5,4-c]pyridine. LCMS (ES) [M+1]⁺ m/z: 397. ¹H NMR(300 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.51 (d, J=0.9 Hz, 1H), 9.01 (d,J=0.9 Hz, 1H), 8.12 (HCOOH), 7.84 (s, 1H), 4.18 (s, 2H), 3.34 (s, 3H),3.18 (t, J=7.3 Hz, 2H), 2.87 (d, J=7.8 Hz, 2H), 2.05-1.97 (m, 2H), 1.24(s, 9H).

Example 1.335 Synthesis ofN-(6-methoxypyridin-3-yl)-2-[methyl(2-{[1,3]thiazolo[5,4-c]pyridin-6-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 329)

Compound 329 was synthesized similar to compound 258 by replacing3-chloro-2,6-naphthyridine with 6-chloro-[1,3]thiazolo[5,4-c]pyridine.LCMS (ES) [M+1]⁺ m/z: 448. ¹H NMR (300 MHz, DMSO-d6) δ 9.71 (s, 1H),9.49 (d, J=0.9 Hz, 1H), 8.93 (d, J=0.9 Hz, 1H), 8.37 (d, J=2.7 Hz, 1H),7.91 (dd, J=8.9, 2.7 Hz, 1H), 6.76 (d, J=8.9 Hz, 1H), 4.47 (s, 2H), 3.79(s, 3H), 3.40 (s, 3H), 3.22 (t, J=7.8 Hz, 2H), 2.87 (t, J=7.8 Hz, 2H),2.07-2.01 (m, 2H).

Example 1.336 Synthesis of2-[(2-{4-[(1-hydroxycyclopropyl)methoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(6-methylpyridin-3-yl)acetamide(Compound 330)

Compound 330 was synthesized similar to Compound 252 by replacing1-(2-hydroxyethyl)pyrrolidine with{1-[(tert-butyldimethylsilyl)oxy]cyclopropyl}methanol and replacing3-fluoroaniline with 6-methyl-3-aminopyridine. LCMS (ES) [M+1]⁺ m/z:461.2. ¹H NMR (300 MHz, DMSO-d₆) δ 10.34 (s, 1H), 8.59 (d, J=2.6 Hz,1H), 8.43 (d, J=5.6 Hz, 1H), 8.17 (s, 1H), 7.99-7.75 (m, 2H), 7.38-6.94(m, 2H), 4.43 (s, 2H), 3.67 (s, 2H), 3.35 (s, 3H), 3.20 (t, J=7.1 Hz,2H), 2.83 (t, J=7.8 Hz, 2H), 2.40 (s, 3H), 2.05-1.95 (m, 2H), 0.93 (d,J=5.1 Hz, 2H), 0.87 (d, J=5.2 Hz, 2H).

Example 1.337 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5,5-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methylpyridin-3-yl)acetamide(Compound 331)

Step 1

Into a 500-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed NaH (6.82 g, 284.19 mmol, 1.10equiv), THE (300.00 mL). To this was added methyl acetoacetate (30.00 g,258.36 mmol, 1.00 equiv) dropwise at 0° C. The resulting solution wasstirred for 15 min at 0° C. To this was added n-BuLi (108.51 mL, 271.27mmol, 1.05 equiv) dropwise with stirring at 0° C. in 15 min. To themixture was added 1-iodo-2-methylpropane (71.32 g, 387.54 mmol, 1.50equiv) dropwise with stirring at 0° C. in 30 min. The resulting solutionwas stirred for 30 min at room temperature. The pH value of the solutionwas adjusted to 6 with HCl (1 mol/L). The resulting solution wasextracted with 3×500 mL of ether and the organic layers combined. Theresulting solution was extracted with 3×500 mL of NaCl and the organiclayers combined and dried over anhydrous sodium sulfate andconcentrated. The residue was applied onto a silica gel column withPE/THF (4%). This resulted in 18 g (40.45%) of methyl6-methyl-3-oxoheptanoate as a yellow liquid.

Step 2

Into a 500-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed methyl 6-methyl-3-oxoheptanoate(18.00 g, 104.52 mmol, 1.00 equiv), CH₃CN (400.00 mL),4-acetamidobenzenesulfonyl azide (25.11 g, 104.52 mmol, 1.00 equiv).This was followed by the addition of Et₃N (31.73 g, 313.55 mmol, 3.00equiv) dropwise with stirring at 0° C. The resulting solution wasstirred for overnight at room temperature. The resulting mixture wasconcentrated. The resulting solution was diluted with 300 mL ofether/n-hexane=1:1. The solids were filtered out. The resulting mixturewas concentrated. The residue was applied onto a silica gel column withTHF/PE (10%). This resulted in 17.8 g (85.92%) of methyl2-diazo-6-methyl-3-oxoheptanoate as a yellow oil.

Step 3

Into a 500-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed Rh₂ (OAc)₄ (0.39 g, 0.87 mmol,0.01 equiv), DCM (250.00 mL). This was followed by the addition of asolution of methyl 2-diazo-6-methyl-3-oxoheptanoate (17.30 g, 87.27mmol, 1.00 equiv) in DCM (50 mL) dropwise with stirring at 0° C. Theresulting solution was stirred for 4 h at room temperature. Theresulting solution was extracted with 3×200 mL of dichloromethane andthe organic layers combined and dried over anhydrous sodium sulfate andconcentrated. The residue was applied onto a silica gel column withTHF/PE (5.6%). This resulted in 12.57 g (84.62%) of methyl2,2-dimethyl-5-oxocyclopentane-1-carboxylate as a dark green liquid.LCMS (ES) [M+1]⁺ m/z: 171.

Step 4

Into a 500-mL round-bottom flask, was placed methyl2,2-dimethyl-5-oxocyclopentane-1-carboxylate (12.00 g, 70.50 mmol, 1.00equiv), urea (12.70 g, 211.47 mmol, 3.00 equiv), EtOH (225.00 mL), HCl(gas) in 1,4-dioxane (45.00 mL). The resulting solution was stirred for3 h at 100° C. The reaction mixture was cooled to room temperature. Theresulting mixture was concentrated. The resulting solution was dilutedwith 200 mL of 5% NaOH. The resulting solution was stirred for 1 h at80° C. The reaction mixture was cooled to 0° C. The pH value of thesolution was adjusted to 3 with HCl (1 mol/L). The solids were collectedby filtration. This resulted in 6.5 g (51.16%) of5,5-dimethyl-1H,3H,6H,7H-cyclopenta[d]pyrimidine-2,4-dione as a greysolid. LCMS (ES) [M−1]⁺ m/z: 179.

Step 5

Into a 250-mL round-bottom flask, was placed5,5-dimethyl-1H,3H,6H,7H-cyclopenta[d]pyrimidine-2,4-dione (6.50 g,36.07 mmol, 1.00 equiv), Et₃N (3.65 g, 36.07 mmol, 1.00 equiv). This wasfollowed by the addition of POCl₃ (80.00 mL) dropwise with stirring atroom temperature. The resulting solution was stirred for 2 h at 80° C.The reaction mixture was cooled to room temperature. The resultingmixture was concentrated. The resulting solution was diluted with 200 mLof water/ice. The pH value of the solution was adjusted to 7-8 withNa₂CO₃. The resulting solution was extracted with 3×200 mL ofdichloromethane and the organic layers combined and dried over anhydroussodium sulfate and concentrated. The residue was applied onto a silicagel column with THF/PE (10%). This resulted in 7.15 g (91.31%) of2,4-dichloro-5,5-dimethyl-6H,7H-cyclopenta[d]pyrimidine as light yellowliquid. LCMS (ES) [M+1]⁺ m/z: 217.

Step 6

Into a 40-mL vial, was placed2,4-dichloro-5,5-dimethyl-6H,7H-cyclopenta[d]pyrimidine (1.00 g, 4.61mmol, 1.00 equiv), 2-(methylamino)-N-(6-methylpyridin-3-yl)acetamide(1.07 g, 5.97 mmol, 1.30 equiv), NMP (20.00 mL), DIEA (2.98 g, 23.03mmol, 5.00 equiv). The resulting solution was stirred for 6 h at 60° C.The reaction mixture was cooled to room temperature. The crude product(3 g) was purified by Prep-HPLC with the following conditions: Column,XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um; mobile phase, Water(0.1% FA) and CAN (20% Phase B up to 60% in 11 min); Detector, 254. Thisresulted in 500 mg (30.16%) of2-([2-chloro-5,5-dimethyl-6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(6-methylpyridin-3-yl)acetamideas off-white solid. LCMS (ES) [M+1]⁺ m/z: 360.

Step 7

Into a 40-mL vial, was placed2-([2-chloro-5,5-dimethyl-6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(6-methylpyridin-3-yl)acetamide(500.00 mg, 1.39 mmol, 1.00 equiv), toluene (10.00 mL),4-fluoro-2-(tributylstannyl)pyridine (804.78 mg, 2.08 mmol, 1.50 equiv),Pd(PPh₃)₄ (160.56 mg, 0.14 mmol, 0.10 equiv). The resulting solution wasstirred for overnight at 120° C. The reaction mixture was cooled to roomtemperature. The resulting mixture was concentrated. The residue wasapplied onto a silica gel column with THF/PE (45%). This resulted in 300mg (51.35%) of2-[[2-(4-fluoropyridin-2-yl)-5,5-dimethyl-6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-N-(6-methylpyridin-3-yl)acetamideas white solid. LCMS (ES) [M+1]⁺ m/z: 421.

Step 8

Into a 40-mL vial, was placed 2-(oxan-2-yloxy)ethanol (208.59 mg, 1.43mmol, 2.00 equiv), DMF (10.00 mL). This was followed by the addition ofNaH (42.80 mg, 1.78 mmol, 2.50 equiv), in portions at 0° C. Theresulting solution was stirred for 0.5 h at room temperature. To thiswas added2-[[2-(4-fluoropyridin-2-yl)-5,5-dimethyl-6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-N-(6-methylpyridin-3-yl)acetamide(300.00 mg, 0.71 mmol, 1.00 equiv), in portions at 0° C. The resultingsolution was stirred for 2 h at room temperature. The reaction was thenquenched by the addition of 20 mL of water/ice. The resulting solutionwas extracted with 3×40 mL of ethyl acetate and the organic layerscombined and dried over anhydrous sodium sulfate and concentrated. Thecrude product (0.5 g) was purified by Prep-HPLC with the followingconditions: Column, XBridge Prep C18 OBD Column, 19 cm, 150 mm, 5 um;mobile phase, Water (0.1% NH₃·H₂O) and CAN (20% Phase B up to 60% in 11min); Detector, 254. This resulted in 230 mg (58.97%) of2-[(5,5-dimethyl-2-[4-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(6-methylpyridin-3-yl)acetamideas off-white solid. LCMS (ES) [M+1]⁺ m/z: 547.

Step 9

Into a 20-mL vial, was placed2-[(5,5-dimethyl-2-[4-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(6-methylpyridin-3-yl)acetamide(230.00 mg, 0.42 mmol, 1.00 equiv), MeOH (5.00 mL), PTSA (36.23 mg, 0.21mmol, 0.50 equiv). The resulting solution was stirred for 1 h at roomtemperature. The crude product (0.2 g) was purified by Prep-HPLC withthe following conditions: Column, XBridge Prep C18 OBD Column, 19 cm,150 mm, 5 um; mobile phase A, Water (0.1% NH₃·H₂O) and mobile phase B,AcCN (20% Phase B up to 60% in 11 min); Detector, 254 nm. This resultedin 166.5 mg (85.56%) of2-([2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5,5-dimethyl-6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(6-methylpyridin-3-yl)acetamideas white solid. LCMS (ES, m/z): [M+H]⁺: 463. ¹H-NMR (300 MHz, DMSO-d₆,ppm): δ 10.51 (s, 1H), 8.59 (d, J=2.6 Hz, 1H), 8.42 (d, J=5.7 Hz, 1H),7.89 (dd, J=8.4, 2.5 Hz, 1H), 7.77 (d, J=2.5 Hz, 1H), 7.16 (d, J=8.4 Hz,1H), 7.01 (dd, J=5.6, 2.5 Hz, 1H), 5.00 (t, J=5.1 Hz, 1H), 4.30 (s, 2H),4.01 (t, J=4.8 Hz, 2H), 3.67 (q, J=4.9 Hz, 2H), 3.32 (s, 3H), 2.88 (t,J=7.3 Hz, 2H), 2.39 (s, 3H), 1.89 (t, J=7.3 Hz, 2H), 1.46 (s, 6H).

Example 1.338 and 1.339 Synthesis of RacemicN-tert-butyl-2-{methyl[2-(4-{[(2S,3S)-2-methyloxetan-3-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 332) and RacemicN-tert-butyl-2-{methyl[2-(4-{[(2R,3S)-2-methyloxetan-3-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 333)

Into a 50-mL 3-necked round-bottom flask, was placed 2-methyloxetan-3-ol(222 mg, 2.52 mmol, 3.00 equiv), DMSO (5 mL). This was followed by theaddition of NaH (101 mg, 2.52 mmol, 3.00 equiv, 60%) at 0° C. Theresulting solution was stirred for 30 min at 25° C. To this was added asolution ofN-tert-butyl-2-[[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamide(300 mg, 0.84 mmol, 1.00 equiv) in DMSO (2 mL) dropwise with stirring at0° C. The resulting solution was stirred for 1 hr at 25° C. The reactionwas then quenched by the addition of 1 mL of water. The crude productwas purified by Prep-HPLC with the following conditions (2 #SHIMADZU(HPLC-01)): Column, Atlantis Prep T3 OBD Column, 19*150 mm 5 um; mobilephase, Water (0.05% TFA) and ACN (16% Phase B up to 30% in 15 min);Detector, UV. 254 nm. This resulted in 108.8 mg (33.78%) of racemicN-tert-butyl-2-[methyl[2-(4-[[(2R,3S)-2-methyloxetan-3-yl]oxy]pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide(Compound 332); tris(trifluoroacetic acid salt) as an off-white solidand 53.7 mg (23.72%) of racemicN-tert-butyl-2-[methyl[2-(4-[[(2S,3S)-2-methyloxetan-3-yl]oxy]pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide(Compound 333); trifluoroacetic acid as an off-white solid.

Compound 332: LCMS (ES) [M+1]⁺ m/z 426. ¹H NMR (300 MHz, DMSO-d₆) δ 8.48(d, J=5.6 Hz, 1H), 7.79 (d, J=2.5 Hz, 1H), 7.69 (s, 1H), 6.91 (dd,J=5.6, 2.6 Hz, 1H), 5.44 (q, J=5.7 Hz, 1H), 5.21 (p, J=6.3 Hz, 1H),4.93-4.83 (m, 1H), 4.49 (dd, J=7.4, 4.8 Hz, 1H), 4.23-4.04 (m, 2H), 3.27(s, 3H), 3.15 (t, J=7.4 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 1.98 (q, J=7.8Hz, 2H), 1.30 (d, J=6.5 Hz, 3H), 1.26 (s, 9H).

Compound 333: LCMS (ES) [M+1]⁺ m/z 426. ¹H NMR (300 MHz, DMSO-d₆) δ 8.69(d, J=5.8 Hz, 1H), 8.04-7.98 (m, 2H), 7.22 (dd, J=5.9, 2.7 Hz, 1H), 5.26(t, J=5.3 Hz, 1H), 4.89 (t, J=6.5 Hz, 2H), 4.40 (t, J=6.4 Hz, 1H), 4.35(s, 2H), 3.47 (s, 3H), 3.25 (s, 2H), 3.04 (t, J=7.9 Hz, 2H), 2.10 (t,J=7.6 Hz, 2H), 1.50 (d, J=6.3 Hz, 3H), 1.27 (s, 9H).

Example 1.340 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(4-methoxyphenyl)-N-methylacetamide(Compound 334)

Compound 334 was synthesized similar to compound 44 by replacingtert-butylamine with 4-methoxy-N-methylaniline. LCMS (ES) [M+1]⁺ m/z:464. ¹H NMR (300 MHz, DMSO-d6) δ 8.52 (d, J=5.7 Hz, 1H), 7.78 (s, 1H),7.48 (d, J=8.4 Hz, 2H), 7.05-7.03 (m, 3H), 4.95 (t J=5.5 Hz, 1H),4.19-4.15 (m, 4H), 3.79 (s, 5H), 3.29 (s, 3H), 3.27-3.22 (m, 5H), 3.14(s, 2H), 2.92-2.71 (m, 2H), 2.13-1.85 (m, 2H).

Example 1.341 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-1-(5-methoxy-2,3-dihydro-1H-indol-1-yl)ethan-1-one(Compound 335)

Compound 335 was synthesized similar to compound 44 by replacingtert-butylamine with 5-methoxy-2,3-dihydro-1H-indole. LCMS (ES) [M+1]⁺m/z: 476. ¹H NMR (300 MHz, DMSO-d6) δ 8.42 (d, J=5.6 Hz, 1H), 7.90 (d,J=8.7 Hz, 1H), 7.70 (d, J=2.5 Hz, 1H), 6.98 (dd, J=5.8, 2.6 Hz, 1H),6.87 (d, J=2.6 Hz, 1H), 6.68 (d, J=8.7 Hz, 1H), 4.88 (t, J=5.3 Hz, 1H),4.57 (s, 2H), 4.25 (t, J=8.3 Hz, 2H), 3.97 (d, J=4.9 Hz, 2H), 3.71 (s,3H), 3.63 (q, J=4.6 Hz, 2H), 3.33 (s, 3H), 3.18 (t, J=7.7 Hz, 4H), 2.82(t, J=7.9 Hz, 2H), 2.02-1.96 (m, 2H).

Example 1.342 Synthesis ofN-tert-butyl-2-[methyl(2-{2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 336)

Compound 336 was synthesized similar to compound 24 by replacing2-tributylstannylpyridine with2-methyl-5-(tributylstannyl)-2H-pyrazolo[3,4-c]pyridine. LCMS (ES+):[M+H]⁺=394.1. ¹H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.03 (s, 1H),8.84 (s, 1H), 8.06 (s, 1H), 4.45-4.32 (m, 6H), 3.51 (s, 2H), 3.09-3.03(m, 2H), 2.15-2.07 (m, 2H), 1.25 (s, 9H).

Example 1.343 Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-[1-(trifluoromethyl)cyclopropyl]acetamide(Compound 337)

Compound 337 was synthesized similar to compound 280 by replacing3-fluoroaniline with 1-(trifluoromethyl)cyclopropan-1-aminehydrochloride. LCMS (ES) [M+1]⁺ m/z: 480. ¹H NMR (300 MHz, DMSO-d6) δ9.07 (s, 1H), 8.46 (d, J=5.6 Hz, 1H), 8.18 (s, HCOOH), 7.76 (d, J=2.5Hz, 1H), 7.05 (dd, J=5.7, 2.6 Hz, 1H), 4.69 (s, 1H), 4.18 (s, 2H), 3.87(s, 2H), 3.28 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H),2.08-1.92 (m, 2H), 1.24 (s, 6H), 1.22-1.07 (m, 2H), 1.04-0.94 (m, 2H).

Example 1.344 Synthesis of2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]-N-[1-(trifluoromethyl)cyclopropyl]acetamide(Compound 338)

Compound 338 was synthesized similar to compound 253 by replacing5-amino-2-methoxypyridine with 1-(trifluoromethyl)cyclopropan-1-aminehydrochloride. LCMS (ES) [M+1]⁺ m/z: 464. ¹H NMR (300 MHz, DMSO-d6) δ8.98 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 7.63 (d, J=2.6 Hz, 1H), 6.89 (dd,J=5.6, 2.6 Hz, 1H), 5.54-5.41 (m, 1H), 5.15-4.91 (m, 2H), 4.64-4.54 (m,2H), 4.18 (s, 2H), 3.33 (s, 3H), 3.16 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.8Hz, 2H), 2.07-1.94 (m, 2H), 1.25-1.14 (m, 2H), 1.03-0.96 (s, 2H).

Example 1.345 Synthesis ofN-(4-chlorophenyl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 339)

Compound 339 was synthesized similar to compound 44 by replacingtert-butylamine with 4-chloroaniline. LCMS (ES) [M+1]⁺ m/z: 454. ¹H NMR(300 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.45 (d, J=5.7 Hz, 1H), 8.14 (s,0.5HCOOH), 7.78 (d, J=2.4 Hz, 1H), 7.64 (d, J=8.9 Hz, 2H), 7.36 (d,J=8.9 Hz, 2H), 7.02 (s, 1H), 4.93 (t, J=5.3 Hz, 1H), 4.43 (s, 2H), 4.05(t, J=4.7 Hz, 2H), 3.69 (d, J=5.0 Hz, 2H), 3.37 (s, 3H), 3.24 (t, J=7.1Hz, 2H), 2.87 (t, J=7.9 Hz, 2H), 2.04-1.93 (m, 2H).

Example 1.346 Synthesis ofN-(4-chlorophenyl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 340)

Compound 340 was synthesized similar to compound 253 by replacing5-amino-2-methoxypyridine with bicyclo[1.1.1]pentan-1-aminehydrochloride. LCMS (ES) [M+1]⁺ m/z: 422. ¹H NMR (300 MHz, DMSO-d₆, ppm)δ 8.70 (s, 1H), 8.50 (dd, J=5.6, 1.4 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H),6.90 (dt, J=5.6, 2.8 Hz, 1H), 5.58-5.43 (m, 1H), 5.05-4.94 (m, 2H), 4.59(dd, J=7.7, 4.8 Hz, 2H), 4.13 (s, 2H), 3.30 (s, 3H), 3.16 (t, J=7.3 Hz,2H), 2.83 (t, J=7.8 Hz, 2H), 2.38 (s, 1H), 2.08-1.97 (m, 2H), 1.98 (s,6H).

Example 1.347 Synthesis ofN-tert-butyl-2-[(2-{furo[3,2-c]pyridin-6-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 341)

Compound 341 was synthesized similar to compound 245 replacing2-chloro-4-(oxetan-3-yloxy)pyridine with 6-chlorofuro[3,2-c]pyridine.LCMS (ES) [M+1]⁺ m/z: 380. ¹H NMR (300 MHz, DMSO-d6) δ 9.03 (s, 1H),8.60 (s, 1H), 8.20 (d, J=2.2 Hz, 2H), 8.15 (s, 0.5HCOOH), 7.79 (s, 1H),7.20-7.13 (m, 1H), 4.15 (s, 2H), 3.32 (s, 3H), 3.17 (t, J=7.4 Hz, 2H),2.84 (t, J=7.8 Hz, 2H), 2.05-1.96 (m, 2H), 1.25 (s, 9H).

Example 1.348 Synthesis of2-[methyl(2-{4-[(3R)-oxolan-3-yloxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]-1-(piperidin-1-yl)ethan-1-one(Compound 342)

Compound 342 was synthesized similar to compound 318 by replacingtert-butylamine with piperidine. LCMS (ES) [M+1]⁺ m/z: 438. ¹H NMR (300MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 8.15 (s, 0.5HCOOH), 7.71 (d,J=2.5 Hz, 1H), 7.04 (dd, J=5.7, 2.6 Hz, 1H), 5.25-5.16 (m, 1H), 4.49 (s,2H), 3.94 (dd, J=10.3, 4.5 Hz, 1H), 3.90-3.73 (m, 3H), 3.52-3.40 (m,4H), 3.25 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.9 Hz, 2H),2.38-2.20 (m, 1H), 2.04-1.94 (m, 3H), 1.71-1.61 (m, 4H), 1.52-1.43 (m,2H).

Example 1.349 Synthesis of2-[methyl(2-{4-[(3S)-oxolan-3-yloxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]-1-(piperidin-1-yl)ethan-1-one(Compound 343)

Compound 343 was synthesized similar to compound 317 by replacingtert-butylamine with piperidine. LCMS (ES) [M+1]⁺ m/z: 438. ¹H NMR (300MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 8.15 (s, 0.5HCOOH), 7.71 (d,J=2.5 Hz, 1H), 7.04 (dd, J=5.7, 2.6 Hz, 1H), 5.25-5.16 (m, 1H), 4.49 (s,2H), 3.94 (dd, J=10.3, 4.5 Hz, 1H), 3.90-3.73 (m, 3H), 3.51-3.41 (m,4H), 3.25 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.9 Hz, 2H),2.38-2.20 (m, 1H), 2.04-1.94 (m, 3H), 1.71-1.61 (m, 4H), 1.52-1.43 (m,2H).

Example 1.350 Synthesis of2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(6-methoxypyridin-3-yl)acetamide(Compound 344)

Compound 344 was synthesized similar to compound 187 by replacingethane-1,2-diol with dimethylaminoethanol. LCMS (ES) [M+1]⁺ m/z: 478. ¹HNMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.44 (d, J=5.6 Hz, 1H), 8.34 (d,J=2.6 Hz, 1H), 8.17 (s, 0.7HCOOH), 7.89 (dd, J=8.9, 2.7 Hz, 1H), 7.76(d, J=2.6 Hz, 1H), 7.01 (dd, J=5.6, 2.6 Hz, 1H), 6.78 (d, J=8.9 Hz, 1H),4.39 (s, 2H), 4.07 (t, J=5.6 Hz, 2H), 3.81 (s, 3H), 3.38 (s, 3H), 3.22(t, J=7.3 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.58 (t, J=5.6 Hz, 2H), 2.20(s, 6H), 2.06-1.99 (m, 2H).

Example 1.351 Synthesis ofN-(3-fluorophenyl)-2-[methyl(2-{4-[(1s,3s)-3-hydroxycyclobutoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 345)

Compound 345 was synthesized similar to compound 280 replacing1-[(2-chloropyridin-4-yl)oxy]-2-methylpropan-2-ol with4-((1s,3s)-3-(benzyloxy)cyclobutoxy)-2-chloropyridine. LCMS (ES) [M+1]⁺m/z: 464. ¹H NMR (300 MHz, DMSO-d6) δ 8.55 (d, J=6.0 Hz, 1H), 7.89 (d,J=2.5 Hz, 1H), 7.55 (d, J=11.5 Hz, 1H), 7.43-7.28 (m, 2H), 7.17 (dd,J=6.1, 2.7 Hz, 1H), 6.92-6.81 (m, 1H), 4.60 (s, 2H), 4.53-4.37 (m, 1H),4.03-3.87 (m, 1H), 3.59 (s, 3H), 3.39 (t, J=7.4 Hz, 2H), 3.08 (t, J=7.9Hz, 2H), 3.00-2.85 (m, 2H), 2.30-2.16 (m, 2H), 2.13-1.98 (m, 2H).

Example 1.352 Synthesis ofN-(6-methoxypyridin-3-yl)-2-[methyl(2-{4-[(3R)-oxolan-3-yloxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 346)

Compound 346 was synthesized similar to compound 187 by replacingethane-1,2-diol with (3R)-oxolan-3-ol. LCMS (ES) [M+1]⁺ m/z: 477. ¹H NMR(300 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.45 (d, J=5.6 Hz, 1H), 8.35 (d,J=2.6 Hz, 1H), 7.89 (dd, J=8.9, 2.7 Hz, 1H), 7.73 (d, J=2.5 Hz, 1H),7.00 (dd, J=5.7, 2.6 Hz, 1H), 6.78 (d, J=8.9 Hz, 1H), 5.13-5.06 (m, 1H),4.39 (s, 2H), 3.80 (s, 3H), 3.90-3.65 (m, 4H), 3.37 (s, 3H), 3.21 (t,J=7.3 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.29-2.11 (m, 1H), 2.09-1.85 (m,3H).

Example 1.353 Synthesis ofN-(6-methoxypyridin-3-yl)-2-[methyl(2-{4-[(3S)-oxolan-3-yloxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 347)

Compound 347 was synthesized similar to compound 187 by replacingethane-1,2-diol with (3S)-oxolan-3-ol. LCMS (ES) [M+1]⁺ m/z: 477. ¹H NMR(300 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.45 (d, J=5.6 Hz, 1H), 8.35 (d,J=2.6 Hz, 1H), 7.89 (dd, J=8.9, 2.7 Hz, 1H), 7.73 (d, J=2.5 Hz, 1H),7.00 (dd, J=5.7, 2.6 Hz, 1H), 6.78 (d, J=8.9 Hz, 1H), 5.13-5.06 (m, 1H),4.39 (s, 2H), 3.80 (s, 3H), 3.90-3.65 (m, 4H), 3.37 (s, 3H), 3.21 (t,J=7.3 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.29-2.11 (m, 1H), 2.09-1.85 (m,3H).

Example 1.354 Synthesis ofN-{bicyclo[1.1.1]pentan-1-yl}-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 349)

Compound 349 was synthesized similar to compound 187 replacing6-methoxypyridin-3-amine with bicyclo[1.1.1]pentan-1-aminehydrochloride. LCMS (ES) [M+1]⁺ m/z: 410. ¹H NMR (300 MHz, DMSO-d6) δ8.73 (s, 1H), 8.47 (d, J=5.6 Hz, 1H), 8.15 (s, 0.5HCOOH), 7.81 (d, J=2.6Hz, 1H), 7.04 (dd, J=5.7, 2.6 Hz, 1H), 4.93 (s, 1H), 4.20-4.09 (m, 4H),3.77 (s, 2H), 3.27 (s, 3H), 3.16 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.8 Hz,2H), 2.37 (s, 1H), 2.05-1.93 (m, 2H), 1.92 (s, 6H).

Example 1.355 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(3-methyl-1,2-thiazol-5-yl)acetamide(Compound 350)

Compound 350 was synthesized similar to compound 187 by replacing6-methoxypyridin-3-amine with 3-methylisothiazol-5-amine hydrochloride.LCMS (ES) [M+1]⁺ m/z: 441. ¹H NMR (300 MHz, DMSO-d6) δ 12.11 (s, 1H),8.45 (d, J=5.7 Hz, 1H), 8.14 (s, HCOOH), 7.68 (d, J=2.7 Hz, 1H), 7.01(dd, J=5.7, 2.4 Hz, 1H), 6.75 (s, 1H), 4.92 (br, 1H), 4.53 (s, 2H), 4.03(t, J=4.8 Hz, 2H), 3.73-3.70 (m, 2H), 3.39 (s, 3H), 3.22 (t, J=7.5 Hz,2H), 2.84 (t, J=7.8 Hz, 2H), 2.30 (s, 3H), 2.04-1.99 (m, 2H).

Example 1.356 Synthesis of2-({2-[4-({[1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}(methyl)amino)-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]pyridin-4-yl}oxy)ethan-1-ol(Compound 351)

Step 1

A solution of 3-fluoroaniline (10.00 g, 89.994 mmol, 1.00 equiv) in amixture of water (50.00 mL) and concentrated hydrochloric acid (30.00mL) was cooled to 0 degrees C. A solution of sodium nitrite (7.45 g,107.992 mmol, 1.20 equiv) in water (10.00 mL) was added maintaining thetemperature between 0 degrees C. and 5 degrees C. Stirring was continuedfor 5 min at 0° C. This solution was added drop wise to a mixture ofacetic acid sodium salt (55.37 g, 674.952 mmol, 7.50 equiv) and ethyl2-isocyanoacetate (11.20 g, 99.013 mmol, 1.10 equiv) in a mixture ofwater (100.00 mL) and methanol (10.00 mL). The reaction mixture wasstirred at 0° C. for 30 min and was allowed to warm to room temperature.Stirring was continued for overnight. The resulting solution wasextracted with 2×300 mL of ethyl acetate. The resulting mixture waswashed with 2×300 of brine. The mixture was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (EA). This resultedin 5.5 g (25.98%) of ethyl1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate as a light yellowsolid. LCMS (ES) [M+1]⁺ m/z: 236.

Into a 250-mL 3-necked round-bottom flask, was placed ethyl1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (5.50 g, 23.383 mmol,1.00 equiv), THE (60.00 mL). This was followed by the addition of LiAlH₄(1.33 g, 35.042 mmol, 1.50 equiv) at 0° C. The resulting solution wasstirred for 1 h at 0° C. The reaction was then quenched by the additionof 1.5 mL of water, 1.5 mL of 15% NaOH, 4.5 mL of water. The mixture wasdried over anhydrous magnesium sulfate. The solids were filtered out.The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(EA). This resulted in 2.2 g (48.70%) of (1-(3-fluorophenyl)-1H-1,2,4-

Step 3

Into a 100-mL 3-necked round-bottom flask, was placed(1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl)methanol (2.00 g, 10.353 mmol,1.00 equiv), DCM (30.00 mL), PCl₅ (4.31 g, 20.697 mmol, 2.00 equiv). Theresulting solution was stirred for 1 h at room temperature. The reactionwas then quenched by the addition of 30 mL of NH₄Cl (aq). The resultingsolution was extracted with 2×40 mL of dichloromethane. The resultingmixture was washed with 2×40 ml of brine. The mixture was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:1). This resulted in 2 g (91.29%) of3-(chloromethyl)-1-(3-fluorophenyl)-1H-1,2,4-triazole as a light yellowsolid. LCMS (ES) [M+1]⁺ m/z: 212.

Step 4

Into a 40-mL round-bottom flask, was placed3-(chloromethyl)-1-(3-fluorophenyl)-1H-1,2,4-triazole (2.00 g, 9.451mmol, 1.00 equiv), MeOH (20.00 mL), Methylamine (2M in methanol, 20.00mL). The resulting solution was stirred for 4 h at 50° C. in an oilbath. The resulting mixture was concentrated under vacuum. The residuewas applied onto a silica gel column with dichloromethane/methanol(10:1). This resulted in 1.5 g (76.96%) of1-(1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl)-N-methylmethanamine as aoff-white solid. LCMS (ES) [M+1]⁺ m/z: 207.

Step 5

Into a 100-mL 3-necked round-bottom flask, was placed2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (1.38 g, 7.300 mmol, 1.00equiv), MeOH (30.00 mL), DIEA (2.35 g, 18.184 mmol, 2.50 equiv). Thiswas followed by the addition of1-(1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl)-N-methylmethanamine (1.50g, 7.274 mmol, 1.00 equiv) at 0° C. The resulting solution was stirredfor 16 h at room temperature. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withdichloromethane/methanol (10:1). This resulted in 1.8 g (68.97%) of2-chloro-N-((1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amineas light yellow oil. LCMS (ES) [M+1]+⁺ m/z: 359.

Step 6

Into a 40-mL sealed tube purged and maintained with an inert atmosphereof nitrogen, was placed2-chloro-N-((1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (200.00 mg, 0.557 mmol, 1.00 equiv), Toluene (6.00mL), 4-fluoro-2-(tributylstannyl)pyridine (322.85 mg, 0.836 mmol, 1.50equiv), Pd(PPh₃)₄ (64.41 mg, 0.056 mmol, 0.10 equiv). The resultingsolution was stirred for 16 h at 100° C. in an oil bath. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with dichloromethane/methanol (10:1). This reactionwas repeated 10 times and obtained 650 mg (69.44%) ofN-((1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-2-(4-fluoropyridin-2-yl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amineas a light yellow oil. LCMS (ES) [M+1]⁺ m/z: 420.

Step 7

Into a 50-mL 3-necked round-bottom flask, was placed ethylene glycol(887.87 mg, 14.305 mmol, 20.00 equiv), DMF (3 mL). This was followed bythe addition of NaH (85.82 mg, 3.576 mmol, 5.00 equiv) at 0 degrees C.To this was addedN-((1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-2-(4-fluoropyridin-2-yl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(300.00 mg, 0.715 mmol, 1.00 equiv) at degrees C. The resulting solutionwas stirred for 2 h at room temperature. The resulting solution wasextracted with 2×20 mL of dichloromethane/methanol (10:1). The resultingmixture was washed with 2×20 ml of brine. The mixture was dried overanhydrous sodium sulfate and concentrated under vacuum. The crudeproduct was purified by Prep-HPLC with the following conditions: SunFirePrep C18 OBD Column, 50*250 mm 5 um 10 nm; mobile phase, phase A: H₂O(0.05% NH₃·H₂O); phase B: CH₃CN (10% CH₃CN up to 50% CH₃CN in 15 min).This resulted in 216.1 mg (65.47%) of2-({2-[4-({[1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}(methyl)amino)-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]pyridin-4-yl}oxy)ethan-1-olas a white solid. LCMS (ES) [M+1]⁺ m/z: 462. ¹H NMR (300 MHz, DMSO-d₆,ppm): δ 9.27 (s, 1H), 8.45 (d, J=5.6 Hz, 1H), 7.86 (d, J=2.6 Hz, 1H),7.80-7.66 (m, 2H), 7.63-7.55 (m, 1H), 7.32-7.19 (m, 1H), 7.02 (dd,J=5.7, 2.6 Hz, 1H), 5.00 (s, 2H), 4.93 (t, J=5.5 Hz, 1H), 4.13 (t, J=4.9Hz, 2H), 3.77-3.72 (m, J=5.0 Hz, 2H), 3.38 (s, 3H), 3.25 (t, J=7.3 Hz,2H), 2.83 (t, J=7.9 Hz, 2H), 2.06-1.95 (m, 2H).

Example 1.357 Synthesis ofN-tert-butyl-2-[methyl({2-[4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide(Compound 352)

Compound 352 was synthesized similar to compound 245 by replacing2-chloro-4-(oxetan-3-yloxy)pyridine with2-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine. LCMS (ES) [M+1]⁺ m/z:420. ¹H NMR (300 MHz, DMSO-d6) δ 8.57 (dd, J=5.1, 0.8 Hz, 1H), 8.47 (s,1H), 8.41 (dd, J=1.8, 0.8 Hz, 1H), 8.14 (d, J=0.8 Hz, 1H), 7.65 (s, 1H),7.60 (dd, J=5.1, 1.8 Hz, 1H), 4.19 (s, 2H), 3.91 (s, 3H), 3.30 (s, 3H),3.17 (t, J=7.4 Hz, 2H), 2.84 (t, J=7.8 Hz, 2H), 2.05-1.95 (m, 2H), 1.18(s, 9H).

Example 1.358 Synthesis ofN-(1-cyclopropyl-1H-pyrazol-4-yl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 353)

Compound 353 was synthesized similar to compound 187 by replacing6-methoxypyridin-3-amine with 1-cyclopropylpyrazol-4-amine. LCMS (ES)[M+1]⁺ m/z: 450. ¹H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.46 (d,J=5.6 Hz, 1H), 7.87 (s, 1H), 7.77 (d, J=2.6 Hz, 1H), 7.40 (s, 1H), 7.02(dd, J=5.6, 2.6 Hz, 1H), 4.94 (s, 1H), 4.35 (s, 2H), 4.07-4.04 (m, 2H),3.71-3.66 (m, 2H), 3.65-3.62 (m, 1H), 3.30 (s, 3H), 3.22-3.16 (m, 2H),2.85-2.80 (m, 2H), 2.02-1.98 (m, 2H), 0.98-0.95 (m, 4H).

Example 1.359 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-1-(pyrrolidin-1-yl)ethan-1-one(Compound 354)

Compound 354 was synthesized similar to compound 187 by replacing6-methoxypyridin-3-amine with pyrrolidine. LCMS (ES) [M+1]⁺ m/z: 398. ¹HNMR (300 MHz, DMSO-d6) δ 8.46 (d, J=5.6 Hz, 1H), 8.15 (s, 1H), 7.72 (d,J=2.5 Hz, 1H), 7.03 (dd, J=5.8, 2.5 Hz, 1H), 4.93 (br, 1H), 4.39 (s,2H), 4.13 (t, J=4.8 Hz, 2H), 3.75 (t, J=4.9 Hz, 2H), 3.54 (t, J=6.8 Hz,2H), 3.34-3.29 (m, 5H), 3.21-3.14 (t, J=7.4 Hz, 2H), 2.92-2.81 (m, 2H),1.96-1.85 (m, 4H), 1.79-1.68 (m, 2H).

Example 1.360 Synthesis of1-(4,4-difluoropiperidin-1-yl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)ethan-1-one(Compound 355)

Compound 355 was synthesized similar to compound 187 by replacing6-methoxypyridin-3-amine with 4,4-difluoropiperidine. LCMS (ES) [M+1]⁺m/z: 448. ¹H NMR (300 MHz, DMSO-d6) δ 8.42 (d, J=5.6 Hz, 1H), 8.16 (s,0.6HCOOH), 7.77 (d, J=2.6 Hz, 1H), 7.03 (dd, J=5.7, 2.6 Hz, 1H), 4.57(s, 2H), 4.12 (t, J=5.0 Hz, 2H), 3.75 (t, J=4.9 Hz, 2H), 3.69-3.52 (m,4H), 3.28 (s, 3H), 3.16 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.9 Hz, 2H),2.23-2.14 (m, 2H), 1.99-2.83 (m, 4H).

Example 1.361 Synthesis of2-({2-[4-(2-acetamidoethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(3-fluorophenyl)acetamide(Compound 356)

Compound 356 was synthesized similar to compound 187 by replacing6-methoxypyridin-3-amine with 3-fluoroaniline and replacingethane-1,2-diol with N-(2-hydroxyethyl)acetamide. LCMS (ES) [M+1]⁺ m/z:479. ¹H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.45 (d, J=5.6 Hz, 1H),8.07 (t, J=5.3 Hz, 1H), 7.78 (d, J=2.5 Hz, 1H), 7.64-7.53 (m, 1H),7.40-7.27 (m, 2H), 7.02 (dd, J=5.7, 2.6 Hz, 1H), 6.86 (ddt, J=8.9, 7.2,2.6 Hz, 1H), 4.45 (s, 2H), 4.05 (t, J=5.5 Hz, 2H), 3.39 (d, J=5.5 Hz,2H), 3.36 (s, 3H), 3.21 (t, J=7.3 Hz, 2H), 2.84 (t, J=7.8 Hz, 2H),2.05-1.96 (m, 2H), 1.83 (s, 3H).

Example 1.362 Synthesis of1-(azepan-1-yl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)ethan-1-one(Compound 357)

Compound 357 was synthesized similar to compound 187 by replacing6-methoxypyridin-3-amine with azepane. LCMS (ES) [M+1]⁺ m/z: 426. ¹H NMR(300 MHz, DMSO-d6) δ 8.44 (d, J=5.6 Hz, 1H), 8.14 (s, 1H), 7.72 (d,J=2.6 Hz, 1H), 7.02 (dd, J=5.6, 2.6 Hz, 1H), 4.92 (s, 1H), 4.54 (s, 2H),4.12 (t, J=4.9 Hz, 2H), 3.80-3.72 (m, 2H), 3.50 (t, J=6.0 Hz, 2H), 3.41(t, J=5.9 Hz, 2H), 3.26 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.9Hz, 2H), 2.03-1.98 (m, 2H), 1.84-1.72 (m, 2H), 1.61-1.40 (m, 6H).

Example 1.363 Synthesis of1-(azepan-1-yl)-2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]ethan-1-one(Compound 358)

Compound 358 was synthesized similar to compound 187 replacing6-methoxypyridin-3-amine with azepane and replacing ethan-1,2-diol withoxetan-3-ol. LCMS (ES) [M+1]⁺ m/z: 438. ¹H NMR (300 MHz, DMSO-d6) δ 8.47(d, J=5.6 Hz, 1H), 7.61 (d, J=2.6 Hz, 1H), 6.87 (dd, J=5.6, 2.6 Hz, 1H),5.50-5.43 (m, 1H), 5.02-4.91 (m, 2H), 4.63-4.52 (m, 4H), 3.50 (t, J=6.0Hz, 2H), 3.42 (t, J=5.9 Hz, 2H), 3.26 (s, 3H), 3.15 (t, J=7.3 Hz, 2H),2.81 (t, J=7.8 Hz, 2H), 2.04-1.94 (m, 2H), 1.88-1.79 (m, 2H), 1.62-1.43(m, 6H).

Example 1.364 Synthesis of1-(4-fluoropiperidin-1-yl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)ethan-1-one(Compound 359)

Compound 359 was synthesized similar to compound 187 by replacing6-methoxypyridin-3-amine with 4-fluoropiperidine. LCMS (ES) [M+1]⁺ m/z:430. ¹H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J=5.4 Hz, 1H), 7.75 (s, 1H),7.02 (dd, J=5.4, 2.5 Hz, 1H), 5.00-4.84 (m, 2H), 4.63-4.45 (m, 2H),4.13-4.10 (m, 2H), 3.76-3.74 (d, J=6 Hz, 2H), 3.70-3.40 (m, 4H), 3.27(s, 3H), 3.17-3.12 (m, 2H), 2.83-2.78 (m, 2H), 2.20-1.50 (m, 6H).

Example 1.365 Synthesis ofN-tert-butyl-2-[ethyl({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide(Compound 360)

Compound 360 was synthesized similar to compound 126. LCMS (ES) [M+1]⁺m/z: 414. ¹H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 7.86 (d,J=2.5 Hz, 1H), 7.70 (s, 1H), 7.04 (dd, J=5.7, 2.5 Hz, 1H), 4.92 (s, 1H),4.19-4.06 (m, 4H), 3.76 (t, J=4.9 Hz, 2H), 3.65 (q, J=7.0 Hz, 2H), 3.07(t, J=7.2 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.05-1.95 (m, 2H), 1.23-1.16(m, 12H).

Example 1.366 Synthesis ofN-tert-butyl-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5,5-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 361)

Compound 361 was synthesized similar to compound 331 by replacing2-(methylamino)-N-(6-methylpyridin-3-yl)acetamide withN-tert-butyl-2-(methylamino)acetamide hydrochloride. LCMS (ES) [M+1]⁺m/z: 428. ¹H NMR (300 MHz, DMSO-d6) δ 8.48 (d, J=5.6 Hz, 1H), 7.86 (d,J=2.6 Hz, 1H), 7.67 (s, 1H), 7.05 (dd, J=5.7, 2.6 Hz, 1H), 4.91 (s, 1H),4.15 (t, J=5.0 Hz, 2H), 4.03 (s, 2H), 3.77 (s, 2H), 3.18 (s, 3H), 2.86(t, J=7.2 Hz, 2H), 1.87 (t, J=7.3 Hz, 2H), 1.43 (s, 6H), 1.21 (s, 9H).

Example 1.367 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5,5-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-1-(piperidin-1-yl)ethan-1-one(Compound 362)

Compound 362 was synthesized similar to compound 331 by replacing2-(methylamino)-N-(6-methylpyridin-3-yl)acetamide with2-(methylamino)-1-(piperidin-1-yl)ethanone hydrochloride. LCMS (ES)[M+1]⁺ m/z: 440. ¹H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=5.6 Hz, 1H),7.72 (d, J=2.6 Hz, 1H), 7.04 (dd, J=5.6, 2.5 Hz, 1H), 4.91 (t, J=5.4 Hz,1H), 4.38 (s, 2H), 4.13 (t, J=4.9 Hz, 2H), 3.76 (q, J=5.1 Hz, 2H), 3.44(d, J=17.6 Hz, 4H), 3.21 (s, 3H), 2.85 (t, J=7.3 Hz, 2H), 1.87 (t, J=7.2Hz, 2H), 1.61 (s, 4H), 1.44 (s, 8H).

Example 1.368 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5,5-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide(Compound 363)

Compound 363 was synthesized similar to compound 331 by replacing2-(methylamino)-N-(6-methylpyridin-3-yl)acetamide withN-(6-methoxypyridin-3-yl)-2-(methylamino)acetamide hydrochloride. LCMS(ES) [M+1]⁺ m/z: 479. ¹H NMR (300 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.42(d, J=5.6 Hz, 1H), 8.33 (d, J=2.6 Hz, 1H), 7.87 (dd, J=9.0, 2.6 Hz, 1H),7.79 (d, J=2.5 Hz, 1H), 7.02 (dd, J=5.7, 2.5 Hz, 1H), 6.77 (d, J=8.8 Hz,1H), 4.91 (s, 1H), 4.29 (s, 2H), 4.02 (t, J=4.8 Hz, 2H), 3.80 (d, J=1.5Hz, 3H), 3.68 (t, J=4.7 Hz, 2H), 3.30 (s, 3H), 2.88 (t, J=7.2 Hz, 2H),1.89 (t, J=7.2 Hz, 2H), 1.46 (s, 6H).

Example 1.369 Synthesis of1-{3-azabicyclo[3.1.1]heptan-3-yl}-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)ethan-1-one(Compound 364)

Compound 364 was synthesized similar to compound 187 by replacing6-methoxypyridin-3-amine with 3-azabicyclo[3.1.1]heptane hydrochloride.LCMS (ES) [M+1]⁺ m/z: 424. ¹H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J=5.7Hz, 1H), 8.17 (s, HCOOH), 7.74 (d, J=2.7 Hz, 1H), 7.04 (dd, J=6.0, 3.0Hz, 1H), 4.50 (s, 2H), 4.14 (t, J=5.1 Hz, 2H), 3.84 (d, J=2.4 Hz, 2H),3.76 (t, J=5.1 Hz, 2H), 3.53 (d, J=2.4 Hz, 2H), 3.31 (s, 3H), 3.17 (t,J=7.2 Hz, 2H), 2.83 (t, J=8.1 Hz, 2H), 2.48-2.43 (m, 2H), 2.19-2.10 (m,2H), 2.03-1.93 (m, 2H), 1.32 (dt, J=6.8, 4.1 Hz, 2H).

Example 1.370 Synthesis ofN-tert-butyl-2-[(2-{furo[2,3-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 365)

Compound 365 was synthesized similar to compound 245 by replacing2-chloro-4-(oxetan-3-yloxy)pyridine with 5-chlorofuro[2,3-c]pyridine.LCMS (ES) [M+1]⁺ m/z: 380. ¹H NMR (300 MHz, DMSO-d6) δ 9.00 (s, 1H),8.73 (s, 1H), 8.32-8.24 (m, 1H), 8.14 (s, 0.5 HCOOH), 7.74 (s, 1H), 7.10(d, J=2.4 Hz, 1H), 4.16 (s, 2H), 3.30 (s, 3H), 3.15 (t, J=7.3 Hz, 2H),2.83 (t, J=7.8 Hz, 2H), 2.05-1.95 (m, 2H), 1.24 (s, 9H).

Example 1.371 Synthesis ofN-tert-butyl-2-[(2-{4-[(2R)-2-hydroxypropoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 366)

Compound 366 was synthesized similar to compound 174 by replacing2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with(2R)-2-(oxan-2-yloxy)propan-1-ol. Analytical chiral HPLC conditions:Column, Lux-cellulose-2, 100*4.6 mm, 3 um; mobile phase A, Ethanol;mobile phase B, CH₃CN; Flow rate: 1 mL/min; Gradient: 20% B in 6 min;254 nm. Retention time: 2.123 min. LCMS (ES) [M+1]⁺ m/z: 414. ¹H NMR(300 MHz, DMSO-d6) δ 8.47 (dd, J=5.7, 1.3 Hz, 1H), 7.99-7.78 (m, 1H),7.69 (s, 1H), 7.05-7.02 (m, 1H), 4.94 (d, J=3.9 Hz, 1H), 4.13 (s, 2H),4.04-3.93 (m, 3H), 3.26 (s, 3H), 3.13 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.8Hz, 2H), 2.03-1.93 (m, 2H), 1.25 (s, 9H), 1.23 (d, J=7.5 Hz, 3H).

Example 1.372 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(2-methylbutan-2-yl)acetamide(Compound 367)

Compound 367 was synthesized similar to compound 44 by replacingtert-butylamine with 2-methylbutan-2-amine. LCMS (ES) [M+1]⁺ m/z: 414.¹H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=5.6 Hz, 1H), 7.84 (d, J=2.5 Hz,1H), 7.49 (s, 1H), 7.04 (dd, J=5.6, 2.6 Hz, 1H), 4.91 (t, J=5.4 Hz, 1H),4.20-4.10 (m, 4H), 3.76 (q, J=5.1 Hz, 2H), 3.25 (s, 3H), 3.14 (t, J=7.2Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.15-1.91 (m, 2H), 1.61 (q, J=7.5 Hz,2H), 1.18 (s, 6H), 0.71 (t, J=7.4 Hz, 3H).

Example 1.373 Synthesis of1-(2,2-dimethylpyrrolidin-1-yl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)ethan-1-one(Compound 368)

Compound 368 was synthesized similar to compound 44 by replacingtert-butylamine with 2,2-dimethylpyrrolidine. LCMS (ES) [M+1]⁺ m/z: 426.¹H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=5.5 Hz, 1H), 7.77 (d, J=2.6 Hz,1H), 7.07-6.99 (m, 1H), 4.91 (s, 1H), 4.30 (s, 2H), 4.13 (t, J=4.9 Hz,2H), 3.78-3.74 (m, 2H), 3.60 (t, J=6.8 Hz, 2H), 3.29 (s, 3H), 3.12 (t,J=7.1 Hz, 2H), 2.80 (t, J=7.8 Hz, 2H), 2.04-1.75 (m, 4H), 1.74-1.69 (m,2H), 1.31 (s, 6H).

Example 1.374 Synthesis ofN-tert-butyl-2-({2-[4-(2-acetamidoethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 369)

Compound 369 was synthesized similar to compound 348 by replacingdimethylaminoethanol with N-(2-hydroxyethyl)acetamide. LCMS (ES) [M+1]⁺m/z: 441. ¹H NMR (300 MHz, DMSO-d6) δ 8.48 (d, J=5.6 Hz, 1H), 8.16 (s,1HCOOH), 8.11 (t, J=5.5 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.68 (s, 1H),7.05 (dd, J=5.6, 2.6 Hz, 1H), 4.17-4.13 (m, 4H), 3.45 (q, J=5.6 Hz, 2H),3.26 (s, 3H), 3.13 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.03-1.96(p, J=7.6 Hz, 2H), 1.84 (s, 3H), 1.24 (s, 9H).

Example 1.375 Synthesis ofN-tert-butyl-2-({2-[4-(2-acetamidoethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 369)

Compound 369 was synthesized similar to compound 348 by replacingdimethylaminoethanol with N-(2-hydroxyethyl)acetamide. LCMS (ES) [M+1]⁺m/z: 441. ¹H NMR (300 MHz, DMSO-d6) δ 8.48 (d, J=5.6 Hz, 1H), 8.16 (s,1HCOOH), 8.11 (t, J=5.5 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.68 (s, 1H),7.05 (dd, J=5.6, 2.6 Hz, 1H), 4.17-4.13 (m, 4H), 3.45 (q, J=5.6 Hz, 2H),3.26 (s, 3H), 3.13 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.03-1.96(p, J=7.6 Hz, 2H), 1.84 (s, 3H), 1.24 (s, 9H).

Example 1.376 Synthesis ofN-tert-butyl-2-[(2-{4-[(2S)-2-hydroxypropoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 370)

Compound 370 was synthesized similar to compound 174 by replacing2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with(2S)-2-(oxan-2-yloxy)propan-1-ol. Analytical chiral HPLC conditions:Column, Lux-cellulose-2, 100*4.6 mm, 3 um; mobile phase A, Ethanol;mobile phase B, CH₃CN; Flow rate: 1 mL/min; Gradient: 20% B in 6 min;254 nm. Retention time: 3.022 min. LCMS (ES) [M+1]⁺ m/z: 414. ¹H NMR(300 MHz, DMSO-d6) δ 8.47 (d, J=5.7 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H),7.68 (s, 1H), 7.04 (dd, J=5.7, 2.4 Hz, 1H), 4.93 (d, J=3.9 Hz, 1H), 4.13(s, 2H), 4.04-3.93 (m, 3H), 3.26 (s, 3H), 3.14 (t, J=7.5 Hz, 2H), 2.81(t, J=7.8 Hz, 2H), 2.04-1.93 (m, 2H), 1.24 (s, 9H), 8.47 (d, J=5.7 Hz,3H).

Example 1.377 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-[(3S)-oxolan-3-yl]acetamide(Compound 371)

Compound 371 was synthesized similar to Compound 135 by replacingoxolan-3-amine with (S)-tetrahydrofuran-3-amine. Analytical chiral HPLCconditions: Column, CHIRALCEL OX-3, 50*4.6 mm, 3 um; mobile phase A,n-Hexane; mobile phase B, Ethanol; Flow rate: 1 mL/min; Gradient: 50% Bin 20 min; 270 nm. Retention time: 7.945 min. LCMS (ES) [M+1]⁺ m/z: 384.¹H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J=5.7 Hz, 1H), 8.38 (d, J=6.9 Hz,1H), 7.81 (d, J=2.7 Hz, 1H), 7.06 (dd, J=5.4, 2.4 Hz, 1H), 4.31-4.25 (m,1H), 4.20 (d, J=2.4 Hz, 2H), 3.90 (s, 3H), 3.78-3.60 (m, 3H), 3.46 (dd,J=9.0, 4.2 Hz, 1H), 3.28 (s, 3H), 3.18 (t, J=7.2 Hz, 2H), 2.85 (t, J=7.8Hz, 2H), 2.11-1.92 (m, 3H), 1.77-1.67 (m, 1H).

Example 1.378 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-[(3R)-oxolan-3-yl]acetamide(Compound 372)

Compound 372 was synthesized similar to Compound 135 by replacingoxolan-3-amine with (R)-tetrahydrofuran-3-amine. Analytical chiral HPLCconditions: Column, CHIRALCEL OX-3, 50*4.6 mm, 3 um; mobile phase A,n-Hexane; mobile phase B, Ethanol; Flow rate: 1 mL/min; Gradient: 50% Bin 20 min; 270 nm. Retention time: 10.028 min. LCMS (ES) [M+1]⁺ m/z:384. ¹H NMR (300 MHz, DMSO-d6) δ 8.48 (d, J=5.7 Hz, 1H), 8.38 (d, J=6.9Hz, 1H), 7.80 (d, J=2.7 Hz, 1H), 7.04 (dd, J=5.4, 2.7 Hz, 1H), 4.31-4.25(m, 1H), 4.20 (d, J=2.7 Hz, 2H), 3.90 (s, 3H), 3.78-3.60 (m, 3H), 3.46(dd, J=9.0, 4.2 Hz, 1H), 3.28 (s, 3H), 3.15 (t, J=7.2 Hz, 2H), 2.82 (t,J=7.8 Hz, 2H), 2.10-1.94 (m, 3H), 1.77-1.67 (m, 1H).

Example 1.379 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-(oxetan-3-yl)acetamide(Compound 373)

Compound 373 was synthesized similar to Compound 135 by replacingoxolan-3-amine with oxetan-3-amine. LCMS (ES) [M+1]⁺ m/z: 370. ¹H NMR(300 MHz, DMSO-d6) δ 8.96 (d, J=6.9 Hz, 1H), 8.48 (d, J=5.4 Hz, 1H),7.79 (d, J=2.7 Hz, 1H), 7.03 (dd, J=5.7, 2.7 Hz, 1H), 4.87-4.78 (m, 1H),4.67 (t, J=6.9 Hz, 2H), 4.43 (t, J=6.3 Hz, 2H), 4.20 (s, 2H), 3.89 (s,3H), 3.29 (s, 3H), 3.16 (t, J=7.2 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H),2.08-1.94 (m, 2H).

Example 1.380 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(oxetan-3-yl)acetamide(Compound 374)

Compound 374 was synthesized similar to Compound 44 by replacingtert-butylamine with oxetan-3-amine. LCMS (ES) [M+1]⁺ m/z: 400. ¹H NMR(300 MHz, DMSO-d6) δ 8.94 (d, J=6.8 Hz, 1H), 8.48 (d, J=5.7 Hz, 1H),7.79 (d, J=2.5 Hz, 1H), 7.04 (dd, J=5.7, 2.6 Hz, 1H), 4.93 (t, J=5.5 Hz,1H), 4.90-4.74 (m, 1H), 4.73-4.63 (m, 2H), 4.44 (t, J=6.3 Hz, 2H), 4.20(s, 2H), 4.14 (t, J=4.9 Hz, 2H), 3.80-3.72 (m, 2H), 3.29 (s, 3H), 3.16(t, J=7.3 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.02-1.97 (m, 2H).

Example 1.381 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-1-{5-methoxy-1H,2H,3H-pyrrolo[2,3-c]pyridin-1-yl}ethan-1-one(Compound 375)

Compound 375 was synthesized similar to Compound 44 by replacingtert-butylamine with 5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine.LCMS (ES) [M+1]⁺ m/z: 477. ¹H NMR (300 MHz, DMSO-d6) δ 8.63 (s, 1H),8.43-8.41 (m, 1H), 8.13 (s, 1HCOOH), 7.69 (s, 1H), 7.02-6.95 (m, 1H),6.77 (m, 1H), 4.89-4.87 (m, 1H), 4.59 (s, 2H), 4.32-4.26 (m, 2H),4.01-3.99 (m, 2H), 3.78 (s, 3H), 3.65-3.63 (m, 2H), 3.38 (s, 3H),3.26-3.20 (m, 4H), 2.86-2.73 (m, 2H), 2.07-1.95 (m, 2H).

Example 1.382 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(1-methylcyclobutyl)acetamide(Compound 376)

Compound 376 was synthesized similar to Compound 44 by replacingtert-butylamine with 1-methylcyclobutan-1-amine. LCMS (ES) [M+1]⁺ m/z:412. ¹H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=5.6 Hz, 1H), 8.15 (s, 1H),7.85 (d, J=2.6 Hz, 1H), 7.04 (dd, J=5.7, 2.6 Hz, 1H), 4.92 (t, J=5.4 Hz,1H), 4.19-4.10 (m, 4H), 3.76 (q, J=5.1 Hz, 2H), 3.27 (s, 3H), 3.15 (t,J=7.2 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.28-2.18 (m, 2H), 2.04-1.95 (m,2H), 1.89-1.78 (m, 2H), 1.78-1.65 (m, 2H), 1.33 (s, 3H).

Example 1.383 Synthesis of2-[(2-{4-[(2R)-2-hydroxypropoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(1-methylcyclobutyl)acetamide(Compound 377)

Compound 377 was synthesized similar to Compound 174 by replacing2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with(2R)-2-(oxan-2-yloxy)propan-1-ol and by replacing tert-butylamine with1-methylcyclobutan-1-amine. Analytical chiral HPLC conditions: Column,Lux-cellulose-2, 100*4.6 mm, 3 um; mobile phase A, Ethanol; mobile phaseB, CH₃CN; Flow rate: 1 mL/min; Gradient: 10% B in 8 min; 254 nm.Retention time: 2.712 min. LCMS (ES) [M+1]⁺ m/z: 426. ¹H NMR (300 MHz,DMSO-d6) δ 8.46 (d, J=5.6 Hz, 1H), 8.14 (s, 1H), 7.84 (d, J=2.6 Hz, 1H),7.04 (dd, J=5.6, 2.6 Hz, 1H), 4.93 (d, J=4.1 Hz, 1H), 4.13 (s, 2H),4.03-3.92 (m, 3H), 3.27 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.9Hz, 2H), 2.27-2.21 (m, 2H), 2.05-1.94 (m, 2H), 1.91-1.76 (m, 2H),1.76-1.65 (m, 2H), 1.34 (s, 3H), 1.18 (d, J=5.8 Hz, 3H).

Example 1.384 Synthesis of2-[(2-{4-[(2S)-2-hydroxypropoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(1-methylcyclobutyl)acetamide(Compound 378)

Compound 378 was synthesized similar to Compound 174 by replacing2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with(2S)-2-(oxan-2-yloxy)propan-1-ol and by replacing tert-butylamine with1-methylcyclobutan-1-amine. Analytical chiral HPLC conditions: Column,Lux-cellulose-2, 100*4.6 mm, 3 um; mobile phase A, Ethanol; mobile phaseB, CH₃CN; Flow rate: 1 mL/min; Gradient: 10% B in 8 min; 254 nm.Retention time: 4.827 min. LCMS (ES) [M+1]⁺ m/z: 426. ¹H NMR (300 MHz,DMSO-d6) δ 8.46 (d, J=5.6 Hz, 1H), 8.14 (s, 1H), 7.84 (d, J=2.6 Hz, 1H),7.04 (dd, J=5.6, 2.6 Hz, 1H), 4.93 (d, J=4.1 Hz, 1H), 4.13 (s, 2H),4.03-3.92 (m, 3H), 3.27 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.9Hz, 2H), 2.27-2.18 (m, 2H), 2.05-1.94 (m, 2H), 1.91-1.76 (m, 2H),1.76-1.65 (m, 2H), 1.34 (s, 3H), 1.18 (d, J=5.8 Hz, 3H).

Example 1.385 Synthesis ofN-[(4-benzyl-1,3-oxazol-2-yl)methyl]-2-(4-methoxypyridin-2-yl)-N-methyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-aminemide(Compound 379)

Step 1

(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid (2 g; 9.75 mmol; 1eq.) was dissolved in N,N-dimethylformamide (40 ml) and cooled in an icebath. 2-Amino-3-phenyl-1-propanol (1.55 g; 10.24 mmol; 1.05 eq.),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU) (5.56 g; 14.62 mmol; 1.5 eq.) andHunig's base (5.1 mL; 29.24 mmol; 3 eq.) were then added. The reactionwas stirred to 25° C. over 3.5 h. Ethyl acetate (100 ml), water andsodium bicarbonate solution (50 ml) were added, the phases wereseparated and the aqueous phase was extracted once (50 ml). The combinedorganics phases were washed with water, saturated sodium chloridesolution and dried over sodium sulfate. After evaporation the residuewas purified by silica gel chromatography (ethyl acetate/hexanesgradient) to give2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-(1-hydroxy-3-phenylpropan-2-yl)acetamide(1.97 g, 60%) as a white solid. LCMS (ES+): [M+H]⁺=339.1.

Step 2

2-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-(1-hydroxy-3-phenylpropan-2-yl)acetamide(1.97 g; 5.82 mmol; 1 eq.) was dissolved in dichloromethane (150 ml) andcooled in an ice bath. 1,1-Bis(acetyloxy)-3-oxo-3H-15,2-benziodaoxol-1-yl acetate (Dess-Martin periodinane) (2.83 g; 6.46mmol; 1.11 eq.) was added and the reaction was stirred to 25° C. over 2h. Sodium bicarbonate solution and sodium thiosulfate solution wereadded and the mixture was stirred for 10 m. The phases were separated,the aqueous phase was extracted with dichloromethane (2×50 ml), thecombined organic phases were washed with saturated sodium chloridesolution and dried over sodium sulfate. Evaporation of solvent gave2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-(1-oxo-3-phenylpropan-2-yl)acetamideas a solid which was used as is. LCMS (ES+): [M+H]⁺=337.1.

Step 3

1,1,1,2,2,2-Hexachloroethane (5.16 g; 21.8 mmol; 2.7 eq.) andtriphenylphosphine (5.76 g; 22 mmol; 2.7 eq.) were dissolved intetrahydrofuran (30 ml) and stirred for 10 m.2-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-(1-oxo-3-phenylpropan-2-yl)acetamide(3.62 g; 8.07 mmol; 1 eq.) suspended in THF (8 ml) was added and themixture was stirred for 10 m. Pyridine (4.18 mL; 51.7 mmol; 6.4 eq.) inTHE (1 ml) was then added dropwise over 15 m. The reaction was stirredin heat block at 80° C. for 18 h. After evaporation, the residue waspurified by silica gel chromatography (ethyl acetate/hexanes gradient)to give2-[(4-benzyl-1,3-oxazol-2-yl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione(1.19 g, 46%) as yellow crystals. LCMS (ES+): [M+H]⁺=319.0.

Step 4

2-[(4-Benzyl-1,3-oxazol-2-yl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione(1.19 g; 3.74 mmol; 1 eq.) was suspended in ethanol (37 ml). Hydrazine(1.7 mL; 18.7 mmol; 5.00 eq.) was added and the reaction was heated in asand bath at 90° C. for 2 h. The reaction was cooled, diluted withethanol (20 ml), filtered and rinsed with more ethanol (20 ml). Afterevaporation the residue was purified by reverse phase chromatography(acetonitrile/water gradient) to give(4-benzyl-1,3-oxazol-2-yl)methanamine (0.31 g, 44%) as an oil. LCMS(ES+): [M+H]⁺=189.1.

Step 5

2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (140 mg; 0.74 mmol;1 eq.) was added to an acetonitrile solution (5 ml) of(4-benzyl-1,3-oxazol-2-yl)methanamine (153 mg; 0.81 mmol; 1.1 eq.)Hunig's base (0.39 mL; 2.22 mmol; 3 eq.) was added and the reaction wasstirred in 60° C. heat block for 66 h. The solvent was evaporated andthe residue was purified by silica gel chromatography (ethylacetate/dichloromethane gradient) to giveN-[(4-benzyl-1,3-oxazol-2-yl)methyl]-2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(107 mg, 42%) as a solid. LCMS (ES+): [M+H]⁺=341.0.

Step 6

N-[(4-Benzyl-1,3-oxazol-2-yl)methyl]-2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(107 mg; 0.31 mmol; 1 eq.) was dissolved in N,N-dimethylformamide (3 ml)and cooled in an ice bath. Iodomethane (195 μL; 3.14 mmol; 10 eq.) wasadded followed by sodium hydride (38 mg; 0.94 mmol; 3 eq.) and stirredto 25° C. over 2.5 h. Water (1 ml), ethyl acetate (50 ml) and sodiumbicarbonate solution (10 ml) were added, the phases were separated andthe aqueous phase was extracted with ethyl acetate (1×10 ml). Thecombined organic phases were washed with water, saturated sodiumchloride solution and dried over sodium sulfate. After evaporation ofsolvent, the residue was purified by silica gel chromatography (ethylacetate/hexanes gradient) to giveN-[(4-benzyl-1,3-oxazol-2-yl)methyl]-2-chloro-N-methyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(92 mg, 83%) as a film. LCMS (ES+): [M+H]⁺=355.0.

Step 7

N-[(4-Benzyl-1,3-oxazol-2-yl)methyl]-2-chloro-N-methyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(63 mg; 0.17 mmol; 1 eq.) was dissolved in toluene (2 ml).4-Methoxy-2-(tributylstannyl)pyridine (156 mg; 0.35 mmol; 2 eq.) in 1 mltoluene was added and the solution was purged with Ar gas.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (14 mg; 17.5 umol; 0.1 eq) was added and thereaction vessel was sealed and stirred in a heat block at 110° C. for 17h. The solvent was evaporated and the residue was purified by reversephase chromatography (Waters XSelect CSH C18 column, 0-90%acetonitrile/0.1% aqueous formic acid gradient) to giveN-[(4-benzyl-1,3-oxazol-2-yl)methyl]-2-(4-methoxypyridin-2-yl)-N-methyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(22 mg, 40%) as a pink solid). LCMS (ES+): [M+H]⁺=428.2. ¹H NMR (400MHz, dmso) δ 8.45 (d, J=5.5 Hz, 1H), 7.78 (s, 2H), 7.73 (s, 1H),7.32-7.12 (m, 5H), 7.01 (d, J=5.5 Hz, 1H), 4.94 (s, 2H), 3.86 (s, 3H),3.77 (s, 2H), 3.20-3.15 (m, 2H), 2.86-2.75 (m, 2H), 2.04-1.89 (m, 2H).

Example 1.386 Synthesis of2-(4-methoxypyridin-2-yl)-N-methyl-N-[(4-phenyl-1,3-oxazol-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(Compound 380)

Compound 380 was synthesized similar to Compound 379 by replacing2-amino-3-phenyl-1-propanol with 2-amino-2-phenylethanol gave2-(4-methoxypyridin-2-yl)-N-methyl-N-[(4-phenyl-1,3-oxazol-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-amineas a tan solid. LCMS (ES+): [M+H]⁺=414.2. ¹H NMR (400 MHz, dmso) δ 8.53(s, 1H), 8.45 (d, J=5.6 Hz, 1H), 7.82 (d, J=2.6 Hz, 1H), 7.77-7.71 (m,2H), 7.44-7.37 (m, 2H), 7.33-7.27 (m, 1H), 7.00 (dd, J=5.6, 2.6 Hz, 1H),5.04 (s, 2H), 3.84 (s, 3H), 3.42 (s, 3H), 3.26-3.22 (m, 2H), 2.87-2.80(m, 2H), 2.06-1.96 (m, 2H).

Example 1.387 Synthesis ofN-tert-butyl-2-[(2-{4-[(1-hydroxycyclopentyl)methoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 381)

Compound 381 was synthesized similar to 174 by replacing2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with[1-(oxan-2-yloxy)cyclopentyl]methanol. LCMS (ES) [M+1]⁺ m/z: 454. ¹H NMR(300 MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 7.83 (d, J=2.5 Hz, 1H),7.67 (s, 1H), 7.05 (dd, J=5.7, 2.6 Hz, 1H), 4.61 (s, 1H), 4.14 (s, 2H),4.01 (s, 2H), 3.26 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.8 Hz,2H), 2.04-1.96 (m, 2H), 1.86-1.51 (m, 8H), 1.25 (s, 9H).

Example 1.388 Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-1-(piperidin-1-yl)ethan-1-oneide(Compound 382)

Compound 382 was synthesized similar to 174 by replacing tert-butylaminewith piperidine. LCMS (ES) [M+1]⁺ m/z: 440. ¹H NMR (300 MHz, DMSO-d6) δ8.45 (d, J=5.6 Hz, 1H), 7.73 (d, J=2.5 Hz, 1H), 7.03 (dd, J=5.7, 2.6 Hz,1H), 4.72 (s, 1H), 4.51 (s, 2H), 3.85 (s, 2H), 3.45 (dt, J=11.2, 5.1 Hz,4H), 3.26 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H),2.06-1.92 (m, 2H), 1.61 (s, 4H), 1.47-1.39 (m, 2H), 1.23 (s, 6H).

Example 1.389 Synthesis ofN-{bicyclo[1.1.1]pentan-1-yl}-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 383)

Compound 383 was synthesized similar to 174 by replacing tert-butylaminewith bicyclo[1.1.1]pentan-1-amine. LCMS (ES) [M+1]⁺ m/z: 438. ¹H NMR(300 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.47 (d, J=5.6 Hz, 1H), 7.79 (d,J=2.6 Hz, 1H), 7.05 (dd, J=5.7, 2.6 Hz, 1H), 4.70 (s, 1H), 4.12 (s, 2H),3.87 (s, 2H), 3.27 (s, 3H), 3.15 (t, J=7.2 Hz, 2H), 2.82 (t, J=7.7 Hz,2H), 2.37 (s, 1H), 2.03-1.91 (m, 7H), 1.24 (s, 6H).

Example 1.390 Synthesis ofN-tert-butyl-2-{[2-(4-{[(2R)-1-hydroxypropan-2-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 384)

Compound 384 was synthesized similar to 174 by replacing2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with(2R)-1-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-ol. Analytical chiralHPLC conditions: Column, CHIRALCEL OX-3, 50*4.6 mm, 3 um; mobile phaseA, n-Hexane; mobile phase B, Ethanol; Flow rate: 1 mL/min; Gradient: 50%B in 10 min; 270 nm. Retention time: 4.949 min. LCMS (ES) [M+1]⁺ m/z:414. ¹H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J=5.4 Hz, 1H), 7.83 (d, J=2.4Hz, 1H), 7.68 (s, 1H), 7.05 (dd, J=5.7, 2.4 Hz, 1H), 4.93 (t, J=5.6 Hz,1H), 4.70-4.60 (m, 1H), 4.18-4.06 (m, 2H), 3.63-3.48 (m, 2H), 3.26 (s,3H), 3.14 (t, J=7.2 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.04-1.93 (m, 2H),1.27 (s, 3H), 1.25 (s, 9H).

Example 1.391 Synthesis ofN-tert-butyl-2-{[2-(4-{[(2S)-1-hydroxypropan-2-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 385)

Compound 385 was synthesized similar to 174 by replacing2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with(2S)-1-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-ol. LCMS (ES) [M+1]⁺ m/z:414. ¹H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J=5.7 Hz, 1H), 7.83 (d, J=2.6Hz, 1H), 7.69 (s, 1H), 7.06 (dd, J=5.7, 2.6 Hz, 1H), 4.93 (t, J=5.6 Hz,1H), 4.69-4.60 (m, 1H), 4.22-4.02 (m, 2H), 3.56 (tq, J=11.5, 6.2, 5.8Hz, 2H), 3.26 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H),2.04-1.96 (m, 2H), 1.24 (d, J=6.1 Hz, 3H), 1.21 (s, 9H).

Example 1.392 Synthesis ofN-tert-butyl-2-[(2-{4-[(2S)-2-hydroxy-3-methylbutoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 386)

Compound 386 was synthesized similar to 174 by replacing2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with(2S)-3-methyl-2-(oxan-2-yloxy)butan-1-ol. Analytical chiral HPLCconditions: Column, Lux-cellulose-2, 100*4.6 mm, 3 um; mobile phase A,AcCN; mobile phase B, Methanol; Flow rate: 1 mL/min; Gradient: 50% B in15 min; 254 nm. Retention time: 9.997 min. LCMS (ES) [M+1]⁺ m/z: 442. ¹HNMR (300 MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 7.83 (d, J=2.5 Hz, 1H),7.66 (s, 1H), 7.06 (dd, J=5.7, 2.6 Hz, 1H), 4.86 (d, J=5.3 Hz, 1H), 4.13(s, 2H), 4.09 (dd, J=10.1, 4.5 Hz, 1H), 4.00 (dd, J=10.1, 6.2 Hz, 1H),3.60 (q, J=5.1 Hz, 1H), 3.26 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.81 (t,J=7.8 Hz, 2H), 2.04-1.96 (p, J=7.7 Hz, 2H), 1.92-1.76 (m, 1H), 1.24 (s,9H), 0.93 (dd, J=6.8, 5.3 Hz, 6H).

Example 1.393 Synthesis ofN-tert-butyl-2-[(2-{4-[(2R)-2-hydroxy-3-methylbutoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 387)

Compound 387 was synthesized similar to 174 by replacing2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with(2R)-3-methyl-2-(oxan-2-yloxy)butan-1-ol. Analytical chiral HPLCconditions: Column, Lux-cellulose-2, 100*4.6 mm, 3 um; mobile phase A,AcCN; mobile phase B, Methanol; Flow rate: 1 mL/min; Gradient: 50% B in15 min; 254 nm. Retention time: 2.582 min. LCMS (ES) [M+1]⁺ m/z: 442. ¹HNMR (300 MHz, DMSO-d6) δ 8.48 (d, J=5.6 Hz, 1H), 7.84 (d, J=2.5 Hz, 1H),7.67 (s, 1H), 7.08 (dd, J=5.7, 2.6 Hz, 1H), 4.87 (d, J=5.3 Hz, 1H), 4.14(s, 2H), 4.09 (J=10.1, 4.5 Hz, 1H), 4.01 (dd, J=10.1, 6.2 Hz, 1H), 3.60(t, J=5.3 Hz, 1H), 3.27 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.8Hz, 2H), 2.02-1.97 (m, 2H), 1.83 (dt, J=13.4, 6.7 Hz, 1H), 1.24 (s, 9H),0.93 (dd, J=6.8, 5.2 Hz, 6H).

Example 1.394 Synthesis ofN-tert-butyl-2-[(2-{4-[(1-hydroxycyclobutyl)methoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 388)

Compound 388 was synthesized similar to 174 by replacing2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with[1-(oxan-2-yloxy)cyclobutyl]methanol. LCMS (ES) [M+1]⁺ m/z: 440. ¹H NMR(300 MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H),7.67 (s, 1H), 7.07 (dd, J=5.7, 2.6 Hz, 1H), 5.29 (s, 1H), 4.13 (s, 2H),4.06 (s, 2H), 3.26 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.8 Hz,2H), 2.17 (d, J=10.2 Hz, 2H), 2.00 (h, J=8.7, 7.8 Hz, 4H), 1.62 (dq,J=19.4, 9.7 Hz, 2H), 1.24 (s, 9H).

Example 1.395 Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(propan-2-yl)acetamide(Compound 389)

Step 1

Into a 1 L round-bottom flask were added 4-chloropicolinimidamidehydrochloride (60.0 g, 312 mmol, 1.00 equiv) in MeOH (600 mL), methyl2-oxocyclopentane-1-carboxylate (66.6 g, 468 mmol, 1.5 equiv), and NaOMe(42.18 g, 781 mmol, 2.5 equiv) in MeOH at room temperature. The mixturewas stirred for 40 hours at 70° C. under a nitrogen atmosphere. Theprecipitated solids were collected by filtration and washed with MeOH(1×1 500 mL). This resulted in2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (62g, 80.12%) as a brown solid. LCMS (ES) [M+1]⁺ m/z 248.

Step 2

Into a 1 L 3-necked round-bottom flask were added2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (60g, 242 mmol, 1.00 equiv) in DCM and TEA (123 g, 1211 mmol, 5.0 equiv). Astirred mixture of Tf₂O (137 g, 484 mmol, 2.0 equiv) in DCM was addeddropwise at 0° C. The resulting mixture was stirred for an additional 2hours at 0° C. The reaction was quenched by the addition of NH₄Cl (aq.500 mL) at room temperature. The resulting mixture was extracted withDCM (3×600 mL), and the organic layer was separated and dried overanhydrous Na₂SO₄. The resulting mixture was filtered and the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with PE/EA (3:1) to afford2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yltrifluoromethanesulfonate (63 g, 68.48%) as an off-white solid. LCMS(ES) [M+1]⁺ m/z 380.

Step 3

Into a 500 mL three-necked round bottom flask were added2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yltrifluoromethanesulfonate (15.0 g, 39.6 mmol, 1.00 equiv), TEA (16.0 g,158.4 mmol, 4.00 equiv), and dichloromethane (300 mL). This was followedby the addition of N-isopropyl-2-(methylamino)acetamide hydrochloride(8.5 g, 51.5 mmol, 1.30 equiv) at room temperature. The mixture wasstirred for 12 h. The reaction was quenched with H₂O (200 mL), andextracted with dichloromethane (2×100 mL). The organic layers werecombined, and dried over anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The residue wastriturated in ethyl acetate/hexane (1:3). The solid was collected byfiltration and dried under an infrared lamp for 3 h. This resulted in13.0 g (91%)2-((2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-isopropylacetamideas an off-white solid. LCMS (ES, m/z): [M+H]⁺: 360.

Step 4

Into a 500 mL three-necked round bottom flask were placed2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (12.6 g, 72.4mmol, 2.00 equiv) and DMSO (150 mL). NaH (60% in mineral oil) (2.9 g,72.4 mmol, 2.00 equiv) was added at ° C. and stirred for 1 h. Afterthat,2-((2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-isopropylacetamide(13.0 g, 36.2 mmol, 1.00 equiv) was added in three portions and themixture was stirred for an additional 3 h at 40° C. The reaction mixturewas cooled to room temperature, quenched with H₂O (200 mL), andextracted with ethyl acetate (3×100 mL). The organic layers werecombined, washed with brine (2×100 mL), and dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by Prep-HPLC with the followingconditions: C18-500 g, CH₃CN/H₂O (NH₄HCO₃ 0.1%), from 15% to 70% in 30min, Flow rate, 150 mL/min, Detector, UV 254 nm. This resulted in 15.0 g(83%)N-isopropyl-2-(methyl(2-(4-(2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamideas a brown solid. LCMS (ES, m/z): [M+H]⁺: 498.

Step 5

Into a 250 mL three-necked round bottom flask were addedN-isopropyl-2-(methyl(2-(4-(2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide(15.0 g, 30.2 mmol, 1.00 equiv), methanol (100 mL), and HCl (c) (5 mL).The mixture was stirred for 0.5 h and diluted with H₂O (200 mL). Its pHwas adjusted to 9 with K₂CO₃ solid, and then extracted withdichloromethane (2×300 mL). The combined organic phases were dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure, the residue was triturated in CH₃CN(120 mL), and the solid was collected by filtration to give 7.38 g2-((2-(4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-isopropylacetamideas a white solid. LCMS (ES, m/z): [M+H]⁺: 414. ¹H-NMR (300 MHz, DMSO-d₆,ppm): δ 8.48 (d, J=5.7 Hz, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.82 (d, J=2.4Hz, 1H), 7.05 (dd, J=5.7, 2.7 Hz, 1H), 4.70 (s, 1H), 4.15 (s, 2H),3.93-3.82 (m, 3H), 3.27 (s, 3H), 3.15 (t, J=7.2 Hz, 2H), 2.82 (t, J=7.8Hz, 2H), 2.04-1.94 (m, 2H), 1.24 (s, 6H), 1.05 (d, J=6.6 Hz, 6H).

Example 1.396 Synthesis ofN-ethyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 390)

Compound 390 was synthesized similar to 389 by replacing propane-2-aminewith ethylamine. LCMS (ES) [M+1]⁺ m/z: 400. ¹H NMR (300 MHz, DMSO-d6) δ8.47 (d, J=5.6 Hz, 1H), 8.18 (t, J=5.1 Hz, 1H), 7.81 (d, J=2.5 Hz, 1H),7.04 (dd, J=5.7, 2.5 Hz, 1H), 4.70 (s, 1H), 4.15 (s, 2H), 3.86 (s, 2H),3.27 (s, 3H), 3.18-3.07 (m, 4H), 2.82 (t, J=7.8 Hz, 2H), 2.04-1.94 (m,2H), 1.23 (s, 6H), 1.04 (t, J=6.6 Hz, 3H).

Example 1.397 Synthesis of1-(4,4-difluoropiperidin-1-yl)-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)ethan-1-one(Compound 391)

Compound 391 was synthesized similar to 389 by replacing propane-2-aminewith ethylamine. LCMS (ES) [M+1]⁺ m/z: 476. ¹H NMR (300 MHz, DMSO-d6) δ8.42 (d, J=5.6 Hz, 1H), 8.15 (s, HCOOH), 7.76 (d, J=2.5 Hz, 1H), 7.03(dd, J=5.6, 2.5 Hz, 1H), 4.71 (s, 1H), 4.58 (s, 2H), 3.85 (s, 2H),3.61-3.54 (m, 4H), 3.29 (s, 3H), 3.17 (t, J=7.2 Hz, 2H), 2.82 (t, J=7.8Hz, 2H), 2.31-2.09 (m, 2H), 1.99-1.79 (m, 4H), 1.22 (s, 6H).

Example 1.398 Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(3-methylpentan-3-yl)acetamide(Compound 392)

Compound 392 was synthesized similar to Compound 44 by replacingIntermediate II with2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(3-methylpentan-3-yl)acetamide.LCMS (ES) [M+1]⁺ m/z: 428. ¹H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=5.6Hz, 1H), 8.16 (s, HCOOH), 7.83 (d, J=2.5 Hz, 1H), 7.33 (s, 1H), 7.03(dd, J=5.6, 2.6 Hz, 1H), 4.20 (s, 2H), 4.14 (t, J=4.9 Hz, 2H), 3.76 (t,J=4.9 Hz, 2H), 3.25 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.9 Hz,2H), 2.03-1.96 (m, 2H), 1.71 (dq, J=14.7, 7.4 Hz, 2H), 1.56-1.38 (m,2H), 1.09 (s, 3H), 0.70 (t, J=7.4 Hz, 6H).

Example 1.399 and Example 1.400 Synthesis ofN-tert-butyl-2-[(2-{4-[(2R)-2-hydroxybutoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 393) andN-tert-butyl-2-[(2-{4-[(2R)-2-hydroxybutoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 394)

Step 1

Into a 20-mL vail were placed2-((tetrahydro-2H-pyran-2-yl)oxy)butan-1-ol (390 mg, 2.24 mmol, 2.00equiv) and DMSO (4.00 mL). NaH (60% in mineral oil) (90 mg, 2.24 mmol,2.00 equiv) was added and the mixture was stirred at room temperaturefor 0.5 h, and addedN-(tert-butyl)-2-((2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(400 mg, 1.12 mmol, 1.00 equiv). The resulting solution was stirred for1 h at room temperature, and then quenched with cooled water, extractedwith 3*30 mL of ethyl acetate. The combined organic phases were washedwith brine (20 mL*2), dried over anhydrous sodium sulfate, filtered andthe filtrate was concentrated under reduced pressure. This resulted in841 mg crude ofN-(tert-butyl)-2-(methyl(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamideas yellow oil and used to the next step without further purification.LCMS (ES)[M+1]⁺ m/z: 512.

Step 2

Into a 50-mL round-bottom flask, was placedN-(tert-butyl)-2-(methyl(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide(841 mg, 1.65 mmol, 1.00 equiv), MeOH (5.0 mL), TsOH (284 mg, 1.65 mmol,1.00 equiv). The mixture was stirred for 1 h at room temperature. Thereaction mixture was purified by Prep-HPLC with the followingconditions: Welch Xtimate C18, 21.2*250 mm, 5 um, Mobile phase, Water(10 mmol/L NH₄HCO₃) and CH₃CN (25% Phase B up to 65% in 15 min),Detector, UV 254 nm. 520 mg ofN-(tert-butyl)-2-((2-(4-(2-hydroxybutoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamidewas obtained as white solid. LCMS (ES)[M+1]⁺ m/z: 428.

Step 3

Chiral HPLC separation: 300 mg ofN-(tert-butyl)-2-((2-(4-(2-hydroxybutoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamidewas separated by Prep-chiral HPLC with the following conditions: Column,Lux 5 um Cellulose-4, 2.12*25 cm, 5 μm, Mobile Phase, MeOH and EtOH (50%Phase B in 23 min), Detector, UV 254 nm. The fraction at 7 min wasfreezing dried, this resulted in 110 mg of(R)—N-(tert-butyl)-2-((2-(4-(2-hydroxybutoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(Compound 393) and The fraction at 16 min, 120 mg(S)—N-(tert-butyl)-2-((2-(4-(2-hydroxybutoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(Compound 394) as a white solid.

Compound 393: Analytical chiral HPLC conditions: Column,Lux-cellulose-4, 100*4.6 mm, 3 um; mobile phase A, Ethanol; mobile phaseB, Methanol; Flow rate: 1 mL/min; Gradient: 50% B in 6 min; 254 nm.Retention time: 2.239 min. LCMS (ES)[M+1]⁺ m/z: 428. ¹H NMR (300 MHz,DMSO-d₆) δ 8.48 (d, J=5.7 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.67 (s, 1H),7.07 (dd, J=5.7, 2.4 Hz, 1H), 4.90 (d, J=5.1 Hz, 1H), 4.13 (s, 2H), 4.00(d, J=5.4 Hz, 2H), 3.77-3.71 (m, 1H), 3.26 (s, 3H), 3.14 (t, J=7.2 Hz,2H), 2.84 (t, J=7.8 Hz, 2H), 2.04-1.94 (m, 2H), 1.66-1.40 (m, 2H), 1.25(s, 9H), 0.96 (t, J=7.5 Hz, 3H).

Compound 394: Analytical chiral HPLC conditions: Column,Lux-cellulose-4, 100*4.6 mm, 3 um; mobile phase A, Ethanol; mobile phaseB, Methanol; Flow rate: 1 mL/min; Gradient: 50% B in 6 min; 254 nm.Retention time: 4.139 min. LCMS (ES)[M+1]⁺ m/z: 428. ¹H NMR (300 MHz,DMSO-d₆) δ 8.48 (d, J=5.7 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.67 (s, 1H),7.07 (dd, J=5.7, 2.4 Hz, 1H), 4.90 (d, J=5.1 Hz, 1H), 4.13 (s, 2H), 4.00(d, J=5.4 Hz, 2H), 3.77-3.71 (m, 1H), 3.26 (s, 3H), 3.14 (t, J=7.2 Hz,2H), 2.84 (t, J=7.8 Hz, 2H), 2.04-1.94 (m, 2H), 1.66-1.40 (m, 2H), 1.25(s, 9H), 0.96 (t, J=7.5 Hz, 3H).

Example 1.401 Synthesis ofN-tert-butyl-2-({2-[4-(2-ethyl-2-hydroxybutoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 395)

Compound 395 was synthesized similar to Compound 174 by replacing2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with2-ethyl-2-(oxan-2-yloxy)butan-1-ol. LCMS (ES) [M+1]⁺ m/z: 456. ¹H NMR(300 MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 7.81 (d, J=2.5 Hz, 1H),7.67 (s, 1H), 7.06 (dd, J=5.7, 2.6 Hz, 1H), 4.41 (s, 1H), 4.13 (s, 2H),3.87 (s, 2H), 3.26 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.9 Hz,2H), 2.07-1.88 (m, 2H), 1.61-1.50 (m, 4H), 1.25 (s, 9H), 0.85 (t, J=7.4Hz, 6H).

Example 1.402 Synthesis ofN-tert-butyl-2-[(2-{4-[(1-hydroxycyclohexyl)methoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 396)

Compound 396 was synthesized similar to Compound 174 by replacing2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with1-(hydroxymethyl)cyclohexan-1-ol. LCMS (ES) [M+1]⁺ m/z: 468. ¹H NMR (300MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 7.82 (d, J=2.5 Hz, 1H), 7.68 (s,1H), 7.06 (dd, J=5.8, 2.5 Hz, 1H), 4.43 (s, 1H), 4.14 (s, 2H), 3.87 (s,2H), 3.27 (s, 3H), 3.15 (t, J=7.2 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H),2.05-1.97 (m, 2H), 1.86-1.33 (m, 9H), 1.25 (s, 9H), 1.25-1.15 (m, 1H).

Example 1.403 Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-[(1R,2S)-2-hydroxycyclopentyl]acetamide(Compound 397)

Compound 397 was synthesized similar to 210 by replacing5-amino-2-methoxypyridine with (1S,2R)-2-aminocyclopentan-1-ol.Analytical chiral HPLC conditions: Column, (S,S)-WHELK-O1, 100*4.6 mm, 3um; mobile phase A, n-Hexane; mobile phase B, ethanol; Flow rate: 1mL/min; Gradient: 50% B in 10 min; 254 nm. Retention time: 3.293 min.LCMS (ES) [M+1]⁺ m/z: 456. ¹H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=5.6Hz, 1H), 7.79 (d, J=2.5 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.04 (dd,J=5.6, 2.6 Hz, 1H), 4.72 (s, 2H), 4.31 (d, J=16.6 Hz, 1H), 4.20 (d,J=16.7 Hz, 1H), 3.94-3.87 (m, 4H), 3.26 (s, 3H), 3.14 (t, J=7.6 Hz, 2H),2.82 (t, J=7.9 Hz, 2H), 2.01-1.96 (m, 2H), 1.81-1.63 (m, 3H), 1.58-1.39(m, 3H), 1.23 (s, 6H).

Example 1.404 Synthesis ofN-cyclopropyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 398)

Compound 398 was synthesized similar to 389 by replacing propane-2-aminewith cyclopropylamine. LCMS (ES) [M+1]⁺ m/z: 412. ¹H NMR (300 MHz,DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 8.25 (d, J=4.1 Hz, 1H), 7.79 (d,J=2.5 Hz, 1H), 7.04 (dd, J=5.7, 2.5 Hz, 1H), 4.70 (s, 1H), 4.14 (s, 2H),3.87 (s, 2H), 3.27 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.8 Hz,2H), 2.63 (dq, J=7.4, 3.8 Hz, 1H), 2.04-1.95 (m, 2H), 1.24 (s, 6H),0.69-0.46 (m, 2H), 0.45-0.39 (m, 2H).

Example 1.405 Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-1-(morpholin-4-yl)ethan-1-oneide(Compound 399)

Compound 399 was synthesized similar to 389 by replacing propane-2-aminewith morpholine. LCMS (ES) [M+1]⁺ m/z: 442. ¹H NMR (300 MHz, DMSO-d6) δ8.46 (d, J=5.6 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.04 (dd, J=5.6, 2.6 Hz,1H), 4.70 (s, 1H), 4.52 (s, 2H), 3.86 (d, J=4.8 Hz, 2H), 3.72-3.41 (m,8H), 3.28 (s, 3H), 3.16 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.9 Hz, 2H),2.11-1.91 (m, 2H), 1.24 (s, 6H).

Example 1.406 Synthesis ofN-tert-butyl-2-[(2-{4-[2-(diethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 400)

Compound 400 was synthesized similar to Compound 348 by replacingDimethylaminoethanol with Diethylaminoethanol. LCMS (ES) [M+1]⁺ m/z:455. ¹H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 7.83 (d, J=2.5Hz, 1H), 7.67 (s, 1H), 7.05 (dd, J=5.6, 2.6 Hz, 1H), 4.16 (t, J=6.1 Hz,2H), 4.13 (s, 2H), 3.26 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.87-2.76 (m,4H), 2.63-2.52 (m, 4H), 2.02-1.99 (m, 2H), 1.25 (s, 9H), 0.98 (t, J=7.1Hz, 6H).

Example 1.407 Synthesis ofN-tert-butyl-2-[methyl(2-{4-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 401)

Compound 401 was synthesized similar to Compound 348 by replacingDimethylaminoethanol with hydroxyethylpyrrolidine. LCMS (ES) [M+1]⁺ m/z:454. ¹H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 7.84 (d, J=2.5Hz, 1H), 7.69 (s, 1H), 7.05 (dd, J=5.6, 2.6 Hz, 1H), 4.21 (t, J=5.8 Hz,2H), 4.13 (s, 2H), 3.27 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.85-2.78 (m,4H), 2.62-2.43 (m, 4H), 2.04-1.94 (m, 2H), 1.77-1.61 (m, 4H), 1.25 (s,9H).

Example 1.408 Synthesis ofN-tert-butyl-2-{[2-(4-{[(2S)-1-(dimethylamino)propan-2-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 402)

Compound 402 was synthesized similar to Compound 348 by replacingDimethylaminoethanol with (S)-1-(dimethylamino)propan-2-ol. LCMS (ES)[M+1]⁺ m/z: 441. ¹H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J=5.6 Hz, 1H),7.82 (d, J=2.5 Hz, 1H), 7.68 (s, 1H), 7.07 (dd, J=5.7, 2.6 Hz, 1H),4.83-4.77 (m, 1H), 4.11 (s, 2H), 3.26 (s, 3H), 3.14 (t, J=7.3 Hz, 2H),2.81 (t, J=7.8 Hz, 2H), 2.59-2.52 (m, 1H), 2.39 (dd, J=12.8, 5.5 Hz,1H), 2.21 (s, 6H), 2.04-1.97 (m, 2H), 1.28 (d, J=6.1 Hz, 3H), 1.25 (s,9H).

Example 1.409 Synthesis of2-{[2-(4-{[(tert-butylcarbamoyl)methyl](methyl)amino}-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl)pyridin-4-yl]oxy}-N,N-dimethylacetamide(Compound 403)

Compound 403 was synthesized similar to Compound 348 by replacingDimethylaminoethanol with 2-hydroxy-N,N-dimethylacetamide. LCMS (ES)[M+1]⁺ m/z: 441. ¹H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J=5.6 Hz, 1H),7.83 (d, J=2.6 Hz, 1H), 7.66 (s, 1H), 6.98 (dd, J=5.7, 2.6 Hz, 1H), 5.00(s, 2H), 4.13 (s, 2H), 3.25 (s, 3H), 3.12 (t, J=7.3 Hz, 2H), 3.01 (s,3H), 2.85 (s, 3H), 2.81 (t, J=7.8 Hz, 2H), 2.01-1.96 (m, 2H), 1.24 (s,9H).

Example 1.410 Synthesis ofN-tert-butyl-2-[(2-{4-[2-(dimethylamino)-2-methylpropoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 404)

Compound 404 was synthesized similar to Compound 348 by replacingDimethylaminoethanol with 2-(dimethylamino)-2-methylpropan-1-ol. LCMS(ES) [M+1]⁺ m/z: 455. ¹H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J=5.6 Hz,1H), 8.20 (s, 2H), 7.83 (d, J=2.5 Hz, 1H), 7.67 (s, 1H), 7.09 (dd,J=5.6, 2.5 Hz, 1H), 4.14 (s, 2H), 4.05 (s, 2H), 3.26 (s, 3H), 3.15 (t,J=7.2 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.36 (s, 6H), 2.04-1.97 (m, 2H),1.25 (s, 9H), 1.19 (s, 6H).

Example 1.411 Synthesis ofN-tert-butyl-2-[(2-{4-[(4-hydroxyoxan-4-yl)methoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 405)

Compound 405 was synthesized similar to Compound 174 by replacing2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with4-(hydroxymethyl)tetrahydro-2H-pyran-4-ol. LCMS (ES) [M+1]⁺ m/z: 470. ¹HNMR (300 MHz, DMSO-d6) δ 8.48 (d, J=5.6 Hz, 1H), 7.84 (d, J=2.6 Hz, 1H),7.67 (s, 1H), 7.06 (dd, J=5.6, 2.6 Hz, 1H), 4.77 (s, 1H), 4.14 (s, 2H),3.92 (s, 2H), 3.76-3.63 (m, 4H), 3.26 (s, 3H), 3.15 (t, J=7.3 Hz, 2H),2.82 (t, J=7.8 Hz, 2H), 2.02-1.93 (m, 2H), 1.86-1.70 (m, 2H), 1.57-1.43(m, 2H), 1.25 (s, 9H).

Example 1.412 Synthesis ofN-tert-butyl-2-{[2-(4-{[(2R)-1-(dimethylamino)propan-2-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 406)

Compound 406 was synthesized similar to Compound 348 by replacingDimethylaminoethanol with (R)-1-(dimethylamino)propan-2-ol. LCMS (ES)[M+1]⁺ m/z: 441. ¹H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J=5.7 Hz, 1H),7.82 (d, J=2.4 Hz, 1H), 7.67 (s, 1H), 7.09 (dd, J=5.7, 2.7 Hz, 1H),4.84-4.78 (m, 1H), 4.12 (s, 2H), 3.27 (s, 3H), 3.15 (t, J=7.2 Hz, 2H),2.84 (t, J=7.8 Hz, 2H), 2.61-2.55 (m, 1H), 2.46-2.40 (m, 1H), 2.23 (s,6H), 2.04-1.94 (m, 2H), 1.30 (d, J=6.0 Hz, 3H), 1.26 (s, 9H).

Example 1.413 Synthesis ofN-tert-butyl-2-{[2-(4-{[1-(dimethylamino)-2-methylpropan-2-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 407)

Compound 407 was synthesized similar to Compound 348 by replacingDimethylaminoethanol with 1-(dimethylamino)-2-methylpropan-2-ol. LCMS(ES) [M+1]⁺ m/z: 455. ¹H NMR (300 MHz, DMSO-d6) δ 8.44 (d, J=5.5 Hz,1H), 7.82 (d, J=2.6 Hz, 1H), 7.63 (s, 1H), 7.09 (dt, J=5.0, 2.1 Hz, 1H),4.15 (s, 2H), 3.24 (s, 3H), 3.13 (t, J=7.4 Hz, 2H), 2.81 (t, J=7.8 Hz,2H), 2.58 (s, 2H), 2.28 (s, 6H), 2.02-1.96 (m, 2H), 1.44 (s, 6H), 1.26(d, J=1.6 Hz, 9H).

Example 1.414 Synthesis of(2R)—N-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]propanamide(Compound 408)

Step 1

Into a 40 mL vial were added(2R)—N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)propanamide(330 mg, 1.06 mmol, 1.00 equiv) and toluene (20 mL),4-fluoro-2-(tributylstannyl)pyridine (615 mg, 1.59 mmol, 1.50 equiv),Pd(PPh₃)₄ (123 mg, 0.10 mmol, 0.10 equiv). The resulting mixture wasstirred for 12 h at 120° C. under nitrogen atmosphere. The resultingmixture was concentrated under vacuum. The residue was purified bysilica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) toafford(2R)—N-tert-butyl-2-{[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}propanamide(240 mg, 61%) as a brown solid. LCMS (ES) [M+1]⁺ m/z: 372.

Step 2

Into a 20 mL vial were added dimethylaminoethanol (115 mg, 1.29 mmol,2.00 equiv) and DMSO (3 mL), To the above mixture was added NaH (60% inmineral oil) (52 mg, 1.29 mmol, 2.00 equiv) in portions. The resultingmixture was stirred for 0.5 h at room temperature. To the above mixturewas added(2R)—N-tert-butyl-2-{[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}propanamide(240 mg, 0.64 mmol, 1.00 equiv) in portions. The resulting mixture wasstirred for additional 1 h at room temperature. The reaction wasquenched with water (1 mL) and purified by Prep-HPLC with the followingconditions: Sunfire Prep C18 OBD Column, 50*250 mm, 5 μm, 10 nm, mobilephase, water (0.1% NH₄OH) and CH₃CN (5% CH₃CN up to 25% in 15 min),Detector, 254 nm UV) to afford(2R)—N-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]propanamide(112.8 mg, 40%) as a white solid. LCMS (ES) [M+1]⁺ m/z: 441. ¹H NMR (300MHz, DMSO-d6) δ 8.49 (d, J=5.6 Hz, 1H), 7.89 (d, J=2.5 Hz, 1H), 7.80 (s,1H), 7.06 (dd, J=5.7, 2.6 Hz, 1H), 5.06 (q, J=7.0 Hz, 1H), 4.21 (t,J=5.7 Hz, 2H), 3.22 (dt, J=15.6, 7.8 Hz, 1H), 3.12 (s, 3H), 3.13-2.99(m, 1H), 2.97-2.72 (m, 2H), 2.66 (t, J=5.7 Hz, 2H), 2.23 (s, 6H),2.06-1.97 (m, 2H), 1.32 (d, J=7.0 Hz, 3H), 1.20 (s, 9H).

Example 1.415 Synthesis ofN-tert-butyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}amino)acetamide(Compound 409)

Compound 409 was synthesized similar to Compound 174 by replacingN-(tert-butyl)-2-(methylamino)acetamide with tert-butyl 2-aminoacetate.LCMS (ES) [M+1]⁺ m/z: 414. ¹H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=5.6Hz, 1H), 7.84 (d, J=2.5 Hz, 1H), 7.69 (s, 1H), 7.14 (t, J=5.9 Hz, 1H),7.04 (dd, J=5.6, 2.6 Hz, 1H), 4.70 (s, 1H), 3.94 (d, J=5.8 Hz, 2H), 3.86(s, 2H), 2.84 (t, J=7.7 Hz, 2H), 2.74 (t, J=7.4 Hz, 2H), 2.09-2.05 (m,2H), 1.25 (s, 9H), 1.24 (s, 6H).

Example 1.416 Synthesis ofN-(1-cyclopropyl-1H-pyrazol-4-yl)-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 410)

Compound 410 was synthesized similar to Compound 348 by replacingtert-butylamine with 1-cyclopropyl-1H-pyrazol-4-amine. LCMS (ES) [M+1]⁺m/z: 477. ¹H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.46 (d, J=5.6 Hz,1H), 7.88 (s, 1H), 7.76 (d, J=2.6 Hz, 1H), 7.39 (s, 1H), 7.02 (dd,J=5.7, 2.5 Hz, 1H), 4.34 (s, 2H), 4.11 (t, J=5.5 Hz, 2H), 3.64 (tt,J=7.2, 4.0 Hz, 1H), 3.32 (s, 3H), 3.19 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.8Hz, 2H), 2.60 (t, J=5.5 Hz, 2H), 2.21 (s, 6H), 2.05-1.95 (m, 2H),1.02-0.83 (m, 4H).

Example 1.417 Synthesis ofN-tert-butyl-2-{methyl[2-(4-{[(2R)-1-methylpyrrolidin-2-yl]methoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 411)

Compound 411 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with (R)-(1-methylpyrrolidin-2-yl)methanol. LCMS(ES) [M+1]⁺ m/z: 453. ¹H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz,1H), 7.82 (d, J=2.4 Hz, 1H), 7.65 (s, 1H), 7.05 (dd, J=5.6, 2.4 Hz, 1H),4.15-4.11 (m, 3H), 4.01-3.96 (m, 1H), 3.26 (s, 3H), 3.16 (t, J=7.2 Hz,2H), 2.99-2.96 (m, 1H), 2.83 (t, J=7.6 Hz, 2H), 2.67-2.65 (m, 1H), 2.40(s, 3H), 2.26-2.24 (m, 1H), 2.02-1.95 (m, 3H), 1.75-1.63 (m, 3H), 1.24(s, 9H).

Example 1.418 Synthesis ofN-tert-butyl-2-{methyl[2-(4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 412)

Compound 412 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with (S)-(1-methylpyrrolidin-2-yl)methanol. LCMS(ES) [M+1]⁺ m/z: 453. ¹H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J=5.4 Hz,1H), 7.82 (d, J=2.4 Hz, 1H), 7.67 (s, 1H), 7.05 (dd, J=5.7, 2.4 Hz, 1H),4.16-4.11 (m, 3H), 4.01-3.97 (m, 1H), 3.26 (s, 3H), 3.16 (t, J=7.2 Hz,2H), 2.99-2.96 (m, 1H), 2.83 (t, J=7.5 Hz, 2H), 2.67-2.65 (m, 1H), 2.40(s, 3H), 2.26-2.24 (m, 1H), 2.02-1.95 (m, 3H), 1.75-1.63 (m, 3H), 1.24(s, 9H).

Example 1.419 Synthesis ofN-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5,5-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 413)

Compound 413 was synthesized similar to Compound 331 by replacing2-(methylamino)-N-(6-methylpyridin-3-yl)acetamide withN-tert-butyl-2-(methylamino)acetamide hydrochloride and by replacingethane-1,2-diol with dimethylaminoethanol. LCMS (ES) [M+1]⁺ m/z: 455. ¹HNMR (300 MHz, DMSO-d6) δ 8.48 (d, J=5.6 Hz, 1H), 7.85 (d, J=2.6 Hz, 1H),7.66 (s, 1H), 7.07 (dd, J=5.6, 2.6 Hz, 1H), 4.20 (t, J=5.7 Hz, 2H), 4.03(s, 2H), 3.19 (s, 3H), 2.86 (t, J=7.3 Hz, 2H), 2.66 (t, J=5.7 Hz, 2H),2.23 (s, 6H), 1.87 (t, J=7.3 Hz, 2H), 1.43 (s, 6H), 1.22 (s, 9H).

Example 1.420 Synthesis ofN-tert-butyl-2-{[2-(4-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 414)

Compound 414 was synthesized similar to Compound 34 by replacing4-methoxy-2-(trimethylstannyl)pyridine with4-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-2-(tributylstannyl)pyridine.LCMS (ES) [M+1]⁺ m/z: 470.2. ¹H NMR (400 MHz, DMSO-d6) δ 8.50-8.47 (m,1H), 7.87-7.85 (m, 1H), 7.69 (s, 1H), 7.08 (dd, J=5.6, 2.6 Hz, 1H),4.48-4.40 (m, 1H), 4.23-4.17 (m, 1H), 4.15-4.06 (m, 4H), 3.79 (dd,J=8.4, 6.4 Hz, 1H), 3.27 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.8Hz, 2H), 2.03-1.95 (m, 2H), 1.37-1.35 (m, 3H), 1.32-1.30 (m, 3H), 1.24(s, 9H).

Example 1.421 Synthesis ofN-tert-butyl-2-[(2-{4-[(2R)-2,3-dihydroxypropoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamidede(Compound 415)

To a solution ofN-Tert-butyl-2-{[2-(4-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(44 mg; 0.09 mmol; 1 eq.) in methanol (1 ml) was added HCl (1 ml of 5-6M HCl in isopropanol). After stirred at 25° C. for 1 h, the mixture wasconcentrated and the residue was purified by reverse phasechromatography (Waters XSelect CSH C18 column, 0-70% acetonitrile/0.1%aqueous formic acid gradient) to giveN-tert-butyl-2-[(2-{4-[(2R)-2,3-dihydroxypropoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(32 mg, 80%) as a solid. LCMS (ES+): [M+H]⁺=470.2. ¹H NMR (400 MHz,DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 7.86-7.82 (m, 1H), 7.69 (s, 1H), 7.04(dd, J=5.7, 2.6 Hz, 1H), 5.01 (d, J=5.1 Hz, 1H), 4.73 (s, 1H), 4.17-4.11(m, 3H), 4.01 (dd, J=10.0, 6.0 Hz, 1H), 3.86-3.79 (m, 1H), 3.49-3.44 (m,2H), 3.26 (s, 3H), 3.16-3.10 (m, 2H), 2.84-2.78 (m, 2H), 2.02-1.94 (m,2H), 1.24 (s, 9H).

Example 1.422 Synthesis ofN-tert-butyl-2-[methyl(2-{4-[(1-methylazetidin-3-yl)oxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 416)

Compound 416 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with 1-methylazetidin-3-ol. LCMS (ES) [M+1]⁺ m/z:425. ¹H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=5.6 Hz, 1H), 7.78 (d, J=2.5Hz, 1H), 7.71 (s, 1H), 6.91 (dd, J=5.6, 2.6 Hz, 1H), 4.95 (q, J=5.6 Hz,1H), 4.12 (s, 2H), 3.83-3.72 (m, 2H), 3.26 (s, 3H), 3.14 (t, J=7.3 Hz,2H), 3.00 (dd, J=8.0, 5.5 Hz, 2H), 2.80 (t, J=7.8 Hz, 2H), 2.30 (s, 3H),2.03-1.96 (m, 2H), 1.26 (s, 9H).

Example 1.423 Synthesis of2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-1-(pyrrolidin-1-yl)ethan-1-one(Compound 417)

Compound 417 was synthesized similar to Compound 348 by replacingtert-butylamine with pyrrolidine. LCMS (ES) [M+1]⁺ m/z: 425. ¹H NMR (300MHz, DMSO-d6) δ 8.46 (d, J=5.6 Hz, 1H), 8.17 (s, HCOOH), 7.69 (d, J=2.6Hz, 1H), 7.04 (dd, J=5.6, 2.6 Hz, 1H), 4.39 (s, 2H), 4.19 (t, J=5.7 Hz,2H), 3.54 (t, J=6.8 Hz, 2H), 3.32 (t, J=6.8 Hz, 2H), 3.29 (s, 3H), 3.15(t, J=7.3 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.68 (t, J=5.6 Hz, 2H), 2.25(s, 6H), 2.06-1.88 (m, 4H), 1.89-1.82 (m, 2H).

Example 1.424 Synthesis of2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-[1-(trifluoromethyl)cyclopropyl]acetamide(Compound 418)

Compound 418 was synthesized similar to Compound 348 by replacingtert-butylamine with 1-(trifluoromethyl)cyclopropan-1-amine. LCMS (ES)[M+1]⁺ m/z: 479. ¹H NMR (300 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.46 (d,J=5.6 Hz, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.05 (dd, J=5.6, 2.6 Hz, 1H),4.25-4.13 (m, 4H), 3.28 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.9Hz, 2H), 2.66 (t, J=5.7 Hz, 2H), 2.23 (s, 6H), 2.04-1.97 (m, 2H),1.24-1.13 (m, 2H), 1.00-0.91 (m, 2H).

Example 1.425 Synthesis ofN-tert-butyl-2-[methyl(2-{4-[2-(methylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 419)

Compound 419 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with tert-butylN-(2-hydroxyethyl)-N-methylcarbamate. LCMS (ES) [M+1]⁺ m/z: 413. ¹H NMR(300 MHz, DMSO-d6) δ 9.36 (br, 2H), 8.76 (d, J=6.0 Hz, 1H), 8.17 (s,1H), 8.11 (br, 1H), 7.50 (dd, J=6.1, 2.6 Hz, 1H), 4.62 (t, J=5.0 Hz,2H), 4.42 (s, 2H), 3.45-3.36 (m, 5H), 3.23 (t, J=7.9 Hz, 2H), 3.01 (t,J=7.9 Hz, 2H), 2.68-2.61 (m, 3H), 2.14-2.03 (m, 2H), 1.25 (s, 9H).

Example 1.426 Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-1-(pyrrolidin-1-yl)ethan-1-one(Compound 420)

Compound 420 was synthesized similar to Compound 389 by replacingpropane-2-amine with pyrrolidine. LCMS (ES) [M+1]⁺ m/z: 426. ¹H NMR (300MHz, DMSO-d6) δ 8.45 (d, J=5.6 Hz, 1H), 7.71 (s, 1H), 7.06-6.99 (m, 1H),4.70 (s, 1H), 4.40 (s, 2H), 3.85 (s, 2H), 3.56 (t, J=6.8 Hz, 2H),3.33-3.31 (m, 2H), 3.30 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.9Hz, 2H), 1.97 (dp, J=14.0, 7.4 Hz, 4H), 1.79 (p, J=6.8 Hz, 2H), 1.22 (s,6H).

Example 1.427 Synthesis ofN-cyclopentyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 421)

Compound 421 was synthesized similar to Compound 389 by replacingpropane-2-amine with 1-cyclopentylamine. LCMS (ES) [M+1]⁺ m/z: 440. ¹HNMR (300 MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 8.28 (s, 1H), 8.09 (d,J=7.5 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.05 (dd, J=5.7, 2.6 Hz, 1H),4.17 (s, 2H), 4.06-3.95 (m, 1H), 3.87 (s, 2H), 3.27 (s, 3H), 3.15 (t,J=7.3 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.02-1.95 (m, 2H), 1.77 (dq,J=13.1, 6.8, 6.2 Hz, 2H), 1.57 (tq, J=5.7, 2.8 Hz, 2H), 1.51-1.31 (m,4H), 1.24 (s, 6H).

Example 1.428 Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-[(3R)-oxolan-3-yl]acetamide(Compound 422)

Compound 422 was synthesized similar to Compound 389 by replacingpropane-2-amine with (R)-tetrahydrofuran-3-amine. LCMS (ES) [M+1]⁺ m/z:442. ¹H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J=5.7 Hz, 1H), 8.40 (d, J=6.9Hz, 1H), 7.81 (d, J=2.4 Hz, 1H), 7.09 (dd, J=5.7, 2.7 Hz, 1H), 4.70 (s,1H), 4.32-4.24 (m, 1H), 4.21 (d, J=1.8 Hz, 2H), 3.88 (s, 2H), 3.78-3.70(m, 2H), 3.67-3.60 (m, 1H), 3.46 (dd, J=8.7, 3.9 Hz, 1H), 3.28 (s, 3H),3.18 (t, J=7.2 Hz, 2H), 2.86 (t, J=7.8 Hz, 2H), 2.11-1.95 (m, 3H),1.78-1.68 (m, 1H), 1.24 (s, 6H).

Example 1.429 Synthesis of2-[(2-{4-[2-(dimethylamino)-2-methylpropoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-[1-(trifluoromethyl)cyclopropyl]acetamide(Compound 423)

Compound 423 was synthesized similar to Compound 348 by replacingtert-butylamine with 1-(trifluoromethyl)cyclopropan-1-amine and byreplacing dimethylaminoethanol with2-(dimethylamino)-2-methylpropan-1-ol. LCMS (ES) [M+1]⁺ m/z: 507. ¹H NMR(300 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.46 (d, J=5.6 Hz, 1H), 7.75 (d,J=2.5 Hz, 1H), 7.07 (dd, J=5.7, 2.5 Hz, 1H), 4.17 (s, 2H), 3.98 (s, 2H),3.29 (s, 3H), 3.15 (t, J=7.4 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.25 (s,6H), 2.06-1.93 (m, 2H), 1.28-1.11 (m, 2H), 1.12 (s, 6H), 1.01-0.92 (m,2H).

Example 1.430 Synthesis of2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-[(3R)-oxolan-3-yl]acetamide(Compound 424)

Step 1

Into a 20 mL vial were added dimethylaminoethanol (354 mg, 3.97 mmol,2.00 equiv), DMSO (5 mL). To the above mixture, NaH (60% in mineral oil)(159 mg, 3.97 mmol, 2.00 equiv). The resulting mixture was stirred for30 min at room temperature, followed by the addition of ethyl2-{[2-(4-fluoropyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4-yl](methyl)amino}acetate(683 mg, 1.98 mmol, 1.00 equiv). The resulting mixture was stirred foradditional 1 h at room temperature. The reaction was quenched with water(2 mL) at room temperature. The mixture was acidified to pH 7 withHCOOH. The residue was purified by reverse phase flash chromatographywith the following conditions: C18-120 g column, H₂O (0.05% FA)/MeCN,10% to 100% gradient in 10 min, detector, UV 254 nm. This resulted inN-(2-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycineformate (410 mg, 53%) as a white solid. LCMS (ES, m/z): [M−HCOOH+H]⁺:372.

Step 2

Into a 20 mL vial were addedN-(2-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycineformate (410 mg, 1.10 mmol, 1.00 equiv), DMF (5 mL), (3R)-oxolan-3-amine(125 mg, 1.43 mmol, 1.30 equiv), DIEA (428 mg, 3.31 mmol, 3.00 equiv).HATU (546 mg, 1.44 mmol, 1.30 equiv) was added at 0° C. The resultingmixture was stirred for 2 h at room temperature. The crude product waspurified by Chiral-Prep-HPLC with the following conditions: XBridgeShield RP18 OBD Column, 19*150 mm, 5 μm, mobile phase, water (0.05%NH₃·H₂O) and CH₃CN (16% up to 33% in 8 min). This resulted in(R)-2-((2-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(tetrahydrofuran-3-yl)acetamide(102.6 mg, 21%) as an off-white solid. LCMS (ES, m/z): [M+H]⁺: 441. ¹HNMR (300 MHz, DMSO-d₆) δ 8.47 (d, J=5.6 Hz, 1H), 8.36 (d, J=6.9 Hz, 1H),7.78 (d, J=2.5 Hz, 1H), 7.05 (dd, J=5.7, 2.6 Hz, 1H), 4.32-4.14 (m, 5H),3.80-3.59 (m, 3H), 3.45 (dd, J=8.9, 4.1 Hz, 1H), 3.28 (s, 3H), 3.16 (t,J=7.3 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.66 (t, J=5.7 Hz, 2H), 2.23 (s,6H), 2.15-1.91 (m, 3H), 1.81-1.65 (m, 1H).

Example 1.431 Synthesis ofN-tert-butyl-2-[(2-{4-[(1-hydroxy-2-methylpropan-2-yl)oxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 425)

Compound 425 was synthesized similar to Compound 44 by replacing4-[2-(oxan-2-yloxy)ethoxy]-2-(trimethylstannyl)pyridine with4-{[2-methyl-1-(oxan-2-yloxy)propan-2-yl]oxy}-2-(tributylstannyl)pyridine.LCMS (ES+): [M+H]⁺=428.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.49-8.42 (m, 1H),7.87-7.80 (m, 1H), 7.69-7.62 (m, 1H), 7.14-7.03 (m, 1H), 5.04 (t, J=5.9Hz, 1H), 4.16-4.11 (m, 2H), 3.86 (s, 1H), 3.50 (d, J=5.8 Hz, 1H),3.27-3.23 (m, 3H), 3.18-3.09 (m, 2H), 2.85-2.77 (m, 2H), 2.04-1.93 (m,2H), 1.39 (s, 3H), 1.24 (s, 9H), 1.23 (s, 3H).

Example 1.432 Synthesis ofN-tert-butyl-2-[methyl({2-[4-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide(Compound 426)

Compound 426 was synthesized similar to Compound 174 by2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with3,3,3-trifluoro-2-(oxan-2-yloxy)propan-1-ol. LCMS (ES+): [M+H]⁺=453.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (d, J=5.6 Hz, 1H), 7.85 (d, J=2.5 Hz,1H), 7.65 (s, 1H), 7.12 (dd, J=5.7, 2.6 Hz, 1H), 6.72 (d, J=6.6 Hz, 1H),4.48-4.39 (m, 1H), 4.36 (dd, J=10.7, 4.1 Hz, 1H), 4.25 (dd, J=10.7, 6.1Hz, 1H), 4.14 (s, 2H), 3.25 (s, 3H), 3.16-3.09 (m, 2H), 2.86-2.78 (m,2H), 2.04-1.93 (m, 2H), 1.23 (s, 9H).

Example 1.433 Synthesis ofN-tert-butyl-2-({2-[4-(2-hydroxyethoxy)-6-methylpyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 427)

Step 1

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a mixture of2-bromo-4-chloro-6-methylpyridine (1.00 g, 4.88 mmol, 1.00 equiv), Tol(30 mL), n-BuLi (2.4 mL, 1.2 equiv) at −78 degrees C., after over 30mins, was added SnBu₃Cl (1.75 g, 5.37 mmol, 1.1 equiv) was dropwised at−78 degrees C. The resulting solution was stirred for 16 hours at −78degrees C. to rt. The resulting mixture was washed with 1×30 ml of NH₄Cland 1×30 ml of aq NaHCO₃, and 1×30 ml of aq. NaCl. The mixture was driedover anhydrous sodium sulfate and concentrated. This resulted in 1.6 g(78.82%) of 4-chloro-2-methyl-6-(tributylstannyl)pyridine as yellow oil.LCMS (ES) [M+1]⁺ m/z 418.

Step 2

Into a 40-mL vial purged and maintained with an inert atmosphere ofnitrogen, was placed a mixture of 2-bromo-4-chloro-6-methylpyridine (1.0g, 23.98 mmol, 1.00 equiv), Toluene (20.0 mL),N-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(710 mg, 23.98 mmol, 1.0 equiv), Pd(PPh₃)₄ (277 mg, 2.40 mmol, 0.10equiv). The resulting solution was stirred for 16 hours at 120 degreesC. The resulting mixture was concentrated. The residue was applied ontoa silica gel column with MeOH/DCM (13/87). This resulted in 800 mg(86.96%) of 4-chloro-2-methyl-6-(tributylstannyl)pyridine as a yellowsolid. LCMS (ES) [M+1]⁺ m/z 388.

Step 3

Into a 8-mL vial, was placed a mixture of NaH (60%) (165 mg, 2.06 mmol,4.00 equiv), DMF (4.0 mL), ethane-1,2-diol (320 mg, 2.58 mmol, 5.0equiv),N-(tert-butyl)-2-((2-(4-chloro-6-methylpyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(200 mg, 0.516 mmol, 1.00 equiv). The resulting solution was stirred for16 hours at 80 degrees C. The reaction was then quenched by the additionof 0.5 mL of water. The crude product was purified by Prep-HPLC with thefollowing conditions: SunFire Prep C18 OBD Column, 30*50 mm, 5 μm 10 nm;Mobile Phase A: Water (0.1% FA), Mobile Phase B: AcCN; Flow rate: 90mL/min; Gradient: 5% B to 35% B in 12 min, 35% B; Wave Length: 220 nm;RT1 (min): 12; Number Of Runs: 0. This resulted in 70 mg (32.86%) ofN-(tert-butyl)-2-((2-(4-(2-hydroxyethoxy)-6-methylpyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideformate as a white solid. LCMS (ES) [M−46+1]⁺ m/z 414. ¹H NMR (400 MHz,DMSO-d6, ppm): δ 8.21 (s, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.65 (s, 1H),6.90 (d, J=2.3 Hz, 1H), 4.15-4.08 (m, 4H), 3.74 (t, J=4.9 Hz, 2H), 3.25(s, 3H), 3.13 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.9 Hz, 2H), 2.48 (s, 3H),2.04-1.92 (m, 1H), 1.23 (s, 9H).

Example 1.434 Synthesis of2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(propan-2-yl)acetamide(Compound 428)

Compound 428 was synthesized similar to Compound 389 by replacing2-methyl-2-(oxan-2-yloxy)propan-1-ol with dimethylaminoethanol. LCMS(ES) [M+1]⁺ m/z: 413. ¹H NMR (300 MHz, DMSO-d6) δ 8.47 (dd, J=5.6, 1.2Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.10-7.00 (m,1H), 4.20 (t, J=5.6 Hz, 2H), 4.15 (s, 2H), 3.94-3.80 (m, 1H), 3.27 (s,3H), 3.15 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.66 (t, J=5.6 Hz,2H), 2.23 (s, 6H), 2.04-1.97 (m, 2H), 1.05 (dd, J=6.6, 1.2 Hz, 6H).

Example 1.435 Synthesis of2-[methyl(2-{4-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]-N-(propan-2-yl)acetamide(Compound 429)

Compound 429 was synthesized similar to Compound 389 by replacing2-methyl-2-(oxan-2-yloxy)propan-1-ol with hydroxyethylpyrrolidine. LCMS(ES) [M+1]⁺ m/z: 439. ¹H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz,1H), 7.99 (d, J=7.8 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.05 (dd, J=5.6,2.6 Hz, 1H), 4.22 (t, J=5.7 Hz, 2H), 4.15 (s, 2H), 3.87 (dq, J=13.5, 6.7Hz, 1H), 3.27 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.87-2.76 (m, 4H),2.59-2.53 (m, 4H), 2.04-1.97 (m, 2H), 1.75-1.61 (m, 4H), 1.04 (d, J=6.6Hz, 6H).

Example 1.436 Synthesis of2-[methyl(2-{4-[2-(morpholin-4-yl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]-N-(propan-2-yl)acetamide(Compound 430)

Compound 430 was synthesized similar to Compound 389 by replacing2-methyl-2-(oxan-2-yloxy)propan-1-ol with 4-morpholineethanol. LCMS (ES)[M+1]⁺ m/z: 455. ¹H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H),7.99 (d, J=7.8 Hz, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.05 (dd, J=5.6, 2.6 Hz,1H), 4.24 (t, J=5.6 Hz, 2H), 4.15 (s, 2H), 3.96-3.78 (m, 1H), 3.64-3.53(m, 4H), 3.27 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H),2.73 (t, J=5.6 Hz, 2H), 2.50-2.47 (m, 4H), 2.04-1.97 (m, 2H), 1.04 (d,J=6.6 Hz, 6H).

Example 1.437 Synthesis of2-[(2-{4-[(1-hydroxycyclopropyl)methoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(propan-2-yl)acetamide(Compound 431)

Compound 431 was synthesized similar to Compound 389 by replacing2-methyl-2-(oxan-2-yloxy)propan-1-ol with(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanol. LCMS (ES) [M+1]⁺m/z: 412. ¹H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 8.00 (d,J=8.0 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.05 (dd, J=5.6, 2.8 Hz, 1H),5.63 (s, 1H), 4.16 (s, 2H), 4.12 (s, 2H), 3.91-3.83 (m, 1H), 3.30 (s,3H), 3.17 (t, J=7.2 Hz, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.03-1.96 (m, 2H),1.05 (d, J=6.4 Hz, 6H), 0.74-0.65 (m, 4H).

Example 1.438 Synthesis of2-[methyl(2-{4-[2-(4-methylpiperazin-1-yl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]-N-(propan-2-yl)acetamide(Compound 432)

Compound 432 was synthesized similar to Compound 389 by replacing2-methyl-2-(oxan-2-yloxy)propan-1-ol with2-(4-methylpiperazin-1-yl)ethanol. LCMS (ES) [M+1]⁺ m/z: 468. ¹H NMR(300 MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 7.99 (d, J=7.7 Hz, 1H),7.80 (d, J=2.5 Hz, 1H), 7.05 (dd, J=5.7, 2.5 Hz, 1H), 4.22 (t, J=5.7 Hz,2H), 4.15 (s, 2H), 3.95-3.81 (m, 1H), 3.27 (s, 3H), 3.15 (t, J=7.3 Hz,2H), 2.82 (t, J=7.8 Hz, 2H), 2.72 (t, J=5.7 Hz, 2H), 2.59-2.50 (m, 4H),2.40-2.28 (m, 4H), 2.15 (s, 3H), 2.04-1.94 (p, J=7.6 Hz, 2H), 1.05 (d,J=6.6 Hz, 6H).

Example 1.439 and Example 1.440 Synthesis of(2R)-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(propan-2-yl)propanamide(Compound 433) and(2S)-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(propan-2-yl)propanamide(Compound 434)

Step 1

Into a 100 mL round-bottom flask were added2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yltrifluoromethanesulfonate (2.5 g, 6.58 mmol, 1.00 equiv),N-isopropyl-2-(methylamino)propanamide (1.42 g, 9.88 mmol, 1.5 equiv),NMP (20 mL), and DIEA (2.55 g, 19.75 mmol, 3 equiv) at room temperature.The resulting mixture was stirred for 4 h at 40° C. The reaction wasquenched with water at room temperature and the resulting mixture wasextracted with EtOAc (3×200 mL). The combined organic layers were washedwith brine (3×200 mL), and dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Thecrude product was recrystallized from EtOAc (100 mL) to afford2-{[2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-isopropylpropanamide(1 g, 40.63%) as a light yellow solid. LCMS (ES) [M+1]⁺ m/z 374.

Step 2

Into a 40 mL vial were added dimethylaminoethanol (238 mg, 2.67 mmol, 2equiv) and DMSO (5 mL) at 0° C. To the above mixture was added NaH (107mg, 2.67 mmol, 2 equiv) in portions at 0° C. The resulting mixture wasstirred for an additional 30 min at room temperature. To the mixture wasthen added2-{[2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-isopropylpropanamide(500 mg, 1.34 mmol, 1.00 equiv) in DMSO dropwise at 0° C. The resultingsolution was stirred for 1 hr at room temperature. The crude product waspurified by Chiral-Prep-HPLC with the following conditions(Prep-HPLC-003): Column, SunFire Prep C18 OBD Column, 19*150 mm, 5 μm 10nm; mobile phase, Water (0.05% TFA) and ACN (35% ACN up to 88% in 8min). The crude product was purified again by Chiral-Prep-HPLC with thefollowing conditions (XA-Prep Chiral HPLC-01): Column, CHIRAL ARTCellulose-SB, 3*25 cm, 5 um; mobile phase, Hex (0.5% 2M NH3-MeOH)— andEtOH (0.5% 2M NH3-MeOH)— (hold 30% EtOH (0.5% 2M NH3-MeOH)— in 12 minThis resulted in(2R)-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-isopropylpropanamide(111.6 mg, 39.13%) and(2S)-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-isopropylpropanamide(114.9 mg, 36.36%) as a white solid.

Compound 433: Analytical chiral HPLC conditions: Column,YMC-cellulose-SB, 100*4.6 mm, 3 um; mobile phase A, n-Hexane; mobilephase B, ethanol; Flow rate: 1 mL/min; Gradient: 10% B in 10 min; 254nm. Retention time: 3.067 min. LCMS (ES) [M+1]⁺ m/z 427. ¹H NMR (400MHz, DMSO-d₆) δ 8.49 (d, J=5.6 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 7.87 (d,J=2.5 Hz, 1H), 7.10-7.04 (m, 1H), 5.07 (q, J=7.0 Hz, 1H), 4.24 (t, J=5.6Hz, 2H), 3.95-3.82 (m, 1H), 3.28-3.15 (m, 1H), 3.11-3.03 (m, 4H),2.95-2.75 (m, 2H), 2.72 (t, J=5.7 Hz, 2H), 2.27 (s, 6H), 2.11-1.88 (m,2H), 1.34 (d, J=7.0 Hz, 3H), 1.08 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz,3H).

Compound 434: Analytical chiral HPLC conditions: Column,YMC-cellulose-SB, 100*4.6 mm, 3 um; mobile phase A, n-Hexane; mobilephase B, ethanol; Flow rate: 1 mL/min; Gradient: 10% B in 10 min; 254nm. Retention time: 4.820 min. LCMS (ES) [M+1]⁺ m/z 427. ¹H NMR (400MHz, DMSO-d₆) δ 8.49 (d, J=5.6 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.17 (s,HCOOH), 7.87 (d, J=2.5 Hz, 1H), 7.10-7.04 (m, 1H), 5.07 (q, J=7.0 Hz,1H), 4.24 (t, J=5.6 Hz, 2H), 3.95-3.82 (m, 1H), 3.28-3.15 (m, 1H), 3.11(s, 4H), 2.95-2.75 (m, 2H), 2.72 (t, J=5.7 Hz, 2H), 2.27 (s, 6H),2.11-1.88 (m, 2H), 1.34 (d, J=7.0 Hz, 3H), 1.08 (d, J=6.6 Hz, 3H), 0.91(d, J=6.6 Hz, 3H).

Example 1.440 Synthesis of(2R)-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(propan-2-yl)propanamide(Compound 433)

Step 1

To a stirred mixture of dimethylaminoethanol (2.10 g, 24.22 mmol, 3.00equiv) in DMSO (30 mL) was added NaH (0.97 g, 24.22 mmol, 3.00 equiv) inportions at room temperature under N₂ atmosphere. The reaction wasstirred at room temperature for 30 min before2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-ol (2.0 g,8.07 mmol, 1.00 equiv) was added. The resulting mixture was stirred at40° C. for 1 h and quenched with H₂O (5 mL) at 15° C. The reactionmixture was purified by prep-HPLC (Column, C18; mobile phase, Mobilephase: MeCN=5/1B: Water Flow rate: 50 mL/min Column: DAICEL CHIRALPAKIC, 250*20 mm, 220 nm Gradient: 50% B in 20 min; 220 nm) to give2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-ol(2.1 g, 86.58%) as an-off white solid. LCMS (ES) [M+1]⁺ m/z: 301.

Step 2

To a stirred solution of2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-ol(2.00 g, 6.66 mmol, 1.00 equiv) and TEA (2.70 g, 26.63 mmol, 4.00 equiv)in DCM (30 mL) was added (CF₃SO₂)₂O (3.76 g, 13.31 mmol, 2.00 equiv)dropwise at 0° C. under N₂ atmosphere. After the reaction was stirred at0-25° C. for 5 h, the reaction was quenched by the addition of water (20mL) at 0° C. The resulting solution was extracted with DCM (50 mL×3),the combined organic layers were washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. This resulted in2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yltrifluoromethanesulfonate (2.6 g, 90.30%) as a brown oil, which was usedin the next step directly.

Step 3

To a stirred solution2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yltrifluoromethanesulfonate (2.50 g, 5.78 mmol, 1.00 equiv) and TEA (2.93g, 28.90 mmol, 5.00 equiv) in DCM (50 mL) was added(2R)—N-isopropyl-2-(methylamino)propanamide hydrochloride (1.57 g, 8.67mmol, 1.50 equiv) in one portion at 25° C., the resulting reaction wasstirred at 25-40° C. for 16 h. The reaction was quenched with water (30mL) at 0° C., extracted with DCM (50 mL×5). The combined organic layerswere washed with brine (50 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Thecrude product (2.1 g) was purified by Prep-HPLC with the followingconditions (Column, C18; mobile phase, Mobile phase: MeCN=5/1B: WaterFlow rate: 40 mL/min Column: DAICEL CHIRALPAK IC, 250*20 mm, 220 nmGradient: 50% B in 25 min; 220 nm)) to afford 750 mg (99.75% purity) ofthe desired product as a white solid. The 750 mg (99.75% purity) of thedesired product was trituration with heptane/EtOAc (50:1, 50 mL) for 1 hand filtered. The filtrate was concentrated to give(2R)-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-isopropylpropanamide(375 mg, 15.21% yield, 99.903% purity) as a white solid. Analyticalchiral HPLC conditions: Column, YMC-cellulose-SB, 100*4.6 mm, 3 um;mobile phase A, n-Hexane; mobile phase B, ethanol; Flow rate: 1 mL/min;Gradient: 10% B in 10 min; 254 nm. Retention time: 3.341 min LCMS (ES)[M+1]⁺ m/z: 427. ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (d, J=5.6 Hz, 1H),8.21 (d, J=8.0 Hz, 1H), 7.86 (d, J=2.5 Hz, 1H), 7.07 (dd, J=5.6, 2.6 Hz,1H), 5.07 (d, J=7.1 Hz, 1H), 4.22 (t, J=5.7 Hz, 2H), 3.89 (dt, J=7.7,6.4 Hz, 1H), 3.26-3.17 (m, 1H), 3.11 (s, 3H), 3.10-3.04 (m, 1H),2.94-2.75 (m, 2H), 2.67 (t, J=5.7 Hz, 2H), 2.23 (s, 6H), 2.10-1.87 (m,2H), 1.34 (d, J=7.0 Hz, 3H), 1.08 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.5 Hz,3H).

Example 1.441 Synthesis of2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5,5-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(propan-2-yl)acetamide(Compound 435)

Compound 435 was synthesized similar to Compound 331 by replacing2-(methylamino)-N-(6-methylpyridin-3-yl)acetamide withN-isopropyl-2-(methylamino)acetamide hydrochloride and by replacingethane-1,2-diol with dimethylaminoethanol. LCMS (ES) [M+1]⁺ m/z: 441. ¹HNMR (400 MHz, DMSO-d₆) δ 8.49 (d, J=5.6 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H),7.81 (d, J=2.5 Hz, 1H), 7.07 (dd, J=5.6, 2.6 Hz, 1H), 4.20 (t, J=5.7 Hz,2H), 4.05 (s, 2H), 3.85 (dq, J=13.5, 6.7 Hz, 1H), 3.20 (s, 3H), 2.87 (t,J=7.3 Hz, 2H), 2.66 (t, J=5.7 Hz, 2H), 2.23 (s, 6H), 1.87 (t, J=7.3 Hz,2H), 1.43 (s, 6H), 1.03 (d, J=6.6 Hz, 6H).

Example 1.442 Synthesis of2-[methyl(2-{4-[2-(3-oxomorpholin-4-yl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]-N-(propan-2-yl)acetamide(Compound 436)

Compound 436 was synthesized similar to Compound 389 by replacing2-methyl-2-(oxan-2-yloxy)propan-1-ol with4-(2-(benzyloxy)ethyl)morpholin-3-one. LCMS (ES) [M+1]⁺ m/z: 469. ¹H NMR(400 MHz, DMSO-d₆) δ 8.50 (d, J=5.6 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H),7.81 (d, J=2.8 Hz, 1H), 7.08 (dd, J=4.8, 2.8 Hz, 1H), 4.32 (t, J=5.6 Hz,2H), 4.15 (s, 2H), 4.05 (s, 2H), 3.92-3.85 (m, 1H), 3.84 (t, J=4.8 Hz,2H), 3.76 (t, J=5.6 Hz, 2H), 3.53 (t, J=5.2 Hz, 2H), 3.27 (s, 3H), 3.17(t, J=7.2 Hz, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.03-1.96 (m, 2H), 1.05 (d,J=6.8 Hz, 6H).

Example 1.443 Synthesis ofN-tert-butyl-2-{methyl[2-(4-{[(3R)-1-methylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 437)

Into a 40 mL vial were added (3R)-1-methylpyrrolidin-3-ol (108 mg, 1.07mmol, 2 equiv) and DMSO (5 mL) at 0° C. To the above mixture was addedNaH (43 mg, 1.07 mmol, 2 equiv) in portions at 0° C. The resultingmixture was stirred for additional 30 min at room temperature and wasaddedN-tert-butyl-2-{[2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(200 mg, 0.54 mmol, 1.00 equiv) in DMSO dropwise at 0° C. The resultingsolution was stirred for 1 hr at room temperature and the crude productwas purified by Chiral-Prep-HPLC with the following conditions(Prep-HPLC-003): Column, SunFire Prep C18 OBD Column, 19*150 mm, 5 μm 10nm; mobile phase, Water (0.1% FA) and ACN (15% ACN up to 55% in 8 min);This resulted inN-tert-butyl-2-{methyl[2-(4-{[(3R)-1-methylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide;(formate) (93.6 mg, 32.98%) as a light brown semi-solid. LCMS (ES)[M+1]⁺ m/z: 439. ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (d, J=5.6 Hz, 1H),7.81 (d, J=2.5 Hz, 1H), 7.69 (s, 1H), 6.99 (dd, J=5.6, 2.6 Hz, 1H),5.10-5.02 (m, 1H), 4.12 (s, 2H), 3.27 (s, 3H), 3.15 (t, J=7.3 Hz, 2H),2.93-2.85 (m, 1H), 2.81 (t, J=7.8 Hz, 2H), 2.75-2.65 (m, 2H), 2.49-2.33(m, 2H), 2.31 (s, 3H), 2.05-1.93 (m, 2H), 1.88-1.77 (m, 1H), 1.25 (s,9H).

Example 1.444 Synthesis ofN-tert-butyl-2-{methyl[2-(4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 438)

Compound 438 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with (3 S)-1-methylpyrrolidin-3-ol. LCMS (ES)[M+1]⁺ m/z: 439. ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (d, J=5.6 Hz, 1H),7.81 (d, J=2.5 Hz, 1H), 7.69 (s, 1H), 6.99 (dd, J=5.6, 2.6 Hz, 1H),5.10-5.02 (m, 1H), 4.12 (s, 2H), 3.27 (s, 3H), 3.15 (t, J=7.3 Hz, 2H),2.93-2.85 (m, 1H), 2.81 (t, J=7.8 Hz, 2H), 2.75-2.65 (m, 2H), 2.49-2.33(m, 2H), 2.31 (s, 3H), 2.05-1.93 (m, 2H), 1.88-1.77 (m, 1H), 1.25 (s,9H).

Example 1.445 Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5,5-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(propan-2-yl)acetamide(Compound 439)

Compound 439 was synthesized similar to Compound 331 by replacing byreplacing 2-(methylamino)-N-(6-methylpyridin-3-yl)acetamide withN-isopropyl-2-(methylamino)acetamide hydrochloride and by replacingethane-1,2-diol with 2-methyl-2-(oxan-2-yloxy)propan-1-ol. LCMS (ES)[M+1]⁺ m/z: 442. ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (d, J=5.6 Hz, 1H),8.18 (d, J=7.8 Hz, 1H), 7.83 (d, J=2.5 Hz, 1H), 7.07 (dd, J=5.7, 2.6 Hz,1H), 4.70 (s, 1H), 4.06 (s, 2H), 3.87 (s, 2H), 3.92-3.79 (m, 1H), 3.20(s, 3H), 2.87 (t, J=7.2 Hz, 2H), 1.88 (t, J=7.3 Hz, 2H), 1.43 (s, 6H),1.24 (s, 6H), 1.02 (d, J=6.6 Hz, 6H).

Example 1.446 Synthesis ofN-tert-butyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)-6-methylpyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 440)

Compound 440 was synthesized similar to Compound 427 by replacing byreplacing ethane-1,2-diol with2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol. LCMS (ES) [M+1]⁺m/z: 442. ¹H NMR (300 MHz, DMSO-d6, ppm): 7.72-7.59 (m, 2H), 6.98-6.88(m, 1H), 4.67 (br, 1H), 4.13 (s, 2H), 3.83 (s, 2H), 3.26 (s, 3H),3.19-3.02 (m, 2H), 2.91-2.74 (m, 2H), 2.50 (s, 3H), 2.13-1.86 (m, 2H),1.45-1.11 (m, 15H).

Example 1.447 Synthesis ofN-ethyl-2-[(2-{4-[(1-hydroxycyclopropyl)methoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 441)

Compound 441 was synthesized similar to Compound 389 by replacing2-methyl-2-(oxan-2-yloxy)propan-1-ol with(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanol and by replacingpropane-2-amine with ethylamine. LCMS (ES) [M+1]⁺ m/z: 398. ¹H NMR (400MHz, DMSO-d₆) δ 8.46 (d, J=5.6 Hz, 1H), 8.15 (t, J=5.8 Hz, 1H), 7.81 (d,J=2.6 Hz, 1H), 7.04 (dd, J=5.6, 2.6 Hz, 1H), 5.64 (s, 1H), 4.17 (s, 2H),4.12 (s, 2H), 3.31 (s, 3H), 3.20-3.09 (m, 4H), 2.82 (t, J=7.9 Hz, 2H),2.03-1.95 (m, 2H), 1.00 (t, J=7.2 Hz, 3H), 0.71 (d, J=3.5 Hz, 2H),0.70-0.63 (m, 2H).

Example 1.448 Synthesis ofN-ethyl-2-({2-[4-(2-ethyl-2-hydroxybutoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 442)

Compound 442 was synthesized similar to Compound 389 by replacing2-methyl-2-(oxan-2-yloxy)propan-1-ol with2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butan-1-ol and by replacingpropane-2-amine with ethylamine. LCMS (ES) [M+1]⁺ m/z: 428. ¹H NMR (300MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 8.18 (t, J=5.7 Hz, 1H), 7.80 (d,J=2.5 Hz, 1H), 7.05 (dd, J=5.7, 2.6 Hz, 1H), 4.43 (s, 1H), 4.17 (s, 2H),3.88 (s, 2H), 3.28 (s, 3H), 3.20-3.07 (m, 4H), 2.82 (t, J=7.8 Hz, 2H),2.04-1.94 (m, 2H), 1.62-1.46 (m, 4H), 1.00 (t, J=7.2 Hz, 3H), 0.85 (t,J=7.5 Hz, 6H).

Example 1.449 Synthesis of2-({2-[4-(2-ethyl-2-hydroxybutoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-methylacetamide(Compound 443)

Compound 443 was synthesized similar to Compound 389 by replacing2-methyl-2-(oxan-2-yloxy)propan-1-ol with2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butan-1-ol and by replacingpropane-2-amine with methylamine. LCMS (ES) [M+1]⁺ m/z: 414. ¹H NMR (400MHz, DMSO-d₆) δ 8.47 (d, J=5.6 Hz, 1H), 8.14 (s, 1HCOOH), 8.12 (d, J=4.9Hz, 1H), 7.78 (d, J=2.5 Hz, 1H), 7.08-7.01 (m, 1H), 4.42 (s, 1H), 4.18(s, 2H), 3.89 (s, 2H), 3.28 (s, 3H), 3.16 (t, J=7.3 Hz, 2H), 2.82 (t,J=7.8 Hz, 2H), 2.63 (d, J=4.5 Hz, 3H), 2.04-1.94 (m, 2H), 1.62-1.48 (m,4H), 0.86 (t, J=7.5 Hz, 6H).

Example 1.450 Synthesis of2-[(2-{4-[(4-hydroxyoxan-4-yl)methoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(propan-2-yl)acetamide(Compound 444)

Compound 444 was synthesized similar to Compound 389 by replacing2-methyl-2-(oxan-2-yloxy)propan-1-ol with(4-(ethoxymethoxy)tetrahydro-2H-pyran-4-yl)methanol. LCMS (ES) [M+1]⁺m/z: 456. ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (d, J=5.6 Hz, 1H), 8.15 (s,1HCOOH), 8.02 (d, J=7.8 Hz, 1H), 7.83 (d, J=2.5 Hz, 1H), 7.06 (dd,J=5.7, 2.6 Hz, 1H), 4.79 (s, 1H), 4.16 (s, 2H), 3.93 (s, 2H), 3.92-3.79(m, 1H), 3.67 (dd, J=7.0, 2.4 Hz, 4H), 3.27 (s, 3H), 3.15 (t, J=7.3 Hz,2H), 2.82 (t, J=7.8 Hz, 2H), 2.04-1.94 (m, 2H), 1.85-1.67 (m, 2H), 1.50(d, J=13.3 Hz, 2H), 1.04 (d, J=6.6 Hz, 6H)

Example 1.451 Synthesis ofN-tert-butyl-2-[(2-{4-[(2R)-2-hydroxy-2-methylbutoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 445)

Compound 445 was synthesized similar to Compound 174 by replacing2-methyl-2-(oxan-2-yloxy)propan-1-ol with(2R)-2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butyl(2S)-2-phenylpropanoate. LCMS (ES) [M+1]⁺ m/z: 442. ¹H NMR (300 MHz,DMSO-d₆) δ 8.48 (d, J=5.4 Hz, 1H), 7.82 (d, J=2.7 Hz, 1H), 7.67 (s, 1H),7.07 (dd, J=5.4, 2.4 Hz, 1H), 4.55 (s, 1H), 4.14 (s, 2H), 3.90 (q,J=12.0, 9.3 Hz, 2H), 3.27 (s, 3H), 3.14 (d, J=7.3 Hz, 2H), 2.82 (t,J=7.8 Hz, 2H), 2.01-1.96 (m, 2H), 1.57 (q, J=7.5 Hz, 2H), 1.25 (s, 9H),1.19 (s, 3H), 0.88 (t, J=7.5 Hz, 3H).

Example 1.452 Synthesis ofN-tert-butyl-2-[(2-{4-[(2R)-2-hydroxy-2-methylbutoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 446)

Compound 446 was synthesized similar to Compound 174 by replacing2-methyl-2-(oxan-2-yloxy)propan-1-ol with(2R)-2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butyl(2S)-2-phenylpropanoate. LCMS (ES) [M+1]⁺ m/z: 442. ¹H NMR (300 MHz,DMSO-d₆) δ 8.48 (d, J=5.4 Hz, 1H), 7.82 (d, J=2.7 Hz, 1H), 7.67 (s, 1H),7.07 (dd, J=5.4, 2.4 Hz, 1H), 4.55 (s, 1H), 4.14 (s, 2H), 3.90 (q,J=12.0, 9.3 Hz, 2H), 3.27 (s, 3H), 3.17 (s, 1H), 3.14 (d, J=7.3 Hz, 2H),2.82 (t, J=7.8 Hz, 2H), 1.99 (p, J=7.7 Hz, 2H), 1.57 (q, J=7.5 Hz, 2H),1.25 (s, 9H), 1.19 (s, 3H), 0.88 (t, J=7.5 Hz, 3H).

Example 1.453 Synthesis ofN-ethyl-2-[(2-{4-[(4-hydroxyoxan-4-yl)methoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 447)

Compound 447 was synthesized similar to Compound 389 by replacing2-methyl-2-(oxan-2-yloxy)propan-1-ol with(4-(ethoxymethoxy)tetrahydro-2H-pyran-4-yl)methanol and by replacingpropane-2-amine with ethylamine. LCMS (ES) [M+1]⁺ m/z: 441. ¹H NMR (300MHz, DMSO-d₆) δ 8.48 (d, J=5.6 Hz, 1H), 8.18 (t, J=5.6 Hz, 1H), 7.82 (d,J=2.5 Hz, 1H), 7.07 (dd, J=5.7, 2.6 Hz, 1H), 4.80 (s, 1H), 4.18 (s, 2H),3.94 (s, 2H), 3.76-3.63 (m, 4H), 3.29 (s, 3H), 3.21-3.05 (m, 4H), 2.83(t, J=7.8 Hz, 2H), 2.05-1.95 (m, 2H), 1.76 (dt, J=13.4, 8.3 Hz, 2H),1.51 (d, J=13.3 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H).

Example 1.454 Synthesis of2-[(2-{4-[(2R)-2-hydroxy-3-methoxypropoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(propan-2-yl)acetamide(Compound 448)

Compound 448 was synthesized similar to Compound 389 by replacing2-methyl-2-(oxan-2-yloxy)propan-1-ol with(2S)-3-methoxy-2-(oxan-2-yloxy)propan-1-ol. LCMS (ES) [M+1]⁺ m/z: 430.¹H NMR (300 MHz, DMSO-d₆) δ 8.47 (d, J=5.6 Hz, 1H), 8.01 (d, J=7.8 Hz,1H), 7.82 (d, J=2.5 Hz, 1H), 7.04 (dd, J=5.6, 2.6 Hz, 1H), 5.19 (d,J=5.0 Hz, 1H), 4.16 (s, 2H), 4.13-3.92 (m, 3H), 3.86 (dt, J=13.5, 6.8Hz, 1H), 3.48-3.38 (m, 2H), 3.30 (s, 3H), 3.27 (s, 3H), 3.15 (t, J=7.3Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.04-1.96 (m, 2H), 1.05 (d, J=6.5 Hz,6H).

Example 1.455 Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-6,6-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(propan-2-yl)acetamide(Compound 449)

Compound 449 was synthesized similar to Compound 389 by replacing methyl2-oxocyclopentane-1-carboxylate with4,4-dimethyl-2-oxocyclopentane-1-carboxylate. LCMS (ES) [M+1]⁺ m/z: 442.¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, J=5.5 Hz, 1H), 8.00 (d, J=7.8 Hz,1H), 7.81 (d, J=2.6 Hz, 1H), 7.04 (dd, J=5.7, 2.7 Hz, 1H), 4.70 (s, 1H),4.13 (s, 2H), 3.92-3.82 (m, 3H), 3.24 (s, 3H), 2.95 (s, 2H), 2.66 (s,2H), 1.24 (s, 6H), 1.15 (s, 6H), 1.05 (d, J=6.6 Hz, 6H).

Example 1.456 Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-7,7-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(propan-2-yl)acetamide(Compound 450)

Compound 450 was synthesized similar to Compound 389 by replacing methyl2-oxocyclopentane-1-carboxylate with3,3-dimethyl-2-oxocyclopentane-1-carboxylate. LCMS (ES) [M+1]⁺ m/z: 442.¹H NMR (300 MHz, DMSO-d₆) δ 8.50 (d, J=5.6 Hz, 1H), 8.02 (d, J=7.8 Hz,1H), 7.81 (d, J=2.5 Hz, 1H), 7.06 (dd, J=5.7, 2.6 Hz, 1H), 4.73 (s, 1H),4.16 (s, 2H), 3.95-3.80 (m, 3H), 3.28 (s, 3H), 3.10 (t, J=7.0 Hz, 2H),1.87 (t, J=7.0 Hz, 2H), 1.23 (d, J=5.9 Hz, 12H), 1.05 (d, J=6.6 Hz, 7H).

Example 1.457 Synthesis ofN-tert-butyl-2-[(2-{4-[(2S)-2,3-dihydroxypropoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 451)

Compound 451 was synthesized similar to Compound 415 by replacingN-Tert-butyl-2-{[2-(4-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamidewithN-Tert-butyl-2-{[2-(4-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide.LCMS (ES) [M+1]⁺ m/z: 430.2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, J=5.6Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.68 (s, 1H), 7.05 (dd, J=5.7, 2.6 Hz,1H), 5.00 (d, J=5.1 Hz, 1H), 4.76-4.67 (m, 1H), 4.18-4.10 (m, 3H), 4.02(dd, J=10.0, 6.0 Hz, 1H), 3.86-3.79 (m, 1H), 3.50-3.44 (m, 2H), 3.26 (s,3H), 3.16-3.10 (m, 2H), 2.84-2.78 (m, 2H), 2.03-1.94 (m, 2H), 1.24 (s,9H).

Example 1.458 Synthesis ofN-tert-butyl-2-[(2-{4-[(2S)-3-fluoro-2-hydroxypropoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 452)

Step 1

(2S)-2-Oxiranylmethanol (28 mg; 0.38 mmol; 1.1 eq.) was dissolved inN,N-dimethylformamide (1.5 ml). and cooled in an ice bath. Sodiumhydride (60%, 30 mg; 0.76 mmol; 2.2 eq.) was added.N-Tert-butyl-2-{[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(123 mg; 0.34 mmol; 1 eq.) (gcxy02152) dissolved in DMF (2 ml) was addedslowly and the reaction was stirred at 25° C. for 18 h. Water (20 ml)was carefully added and the mixture was extracted with ethyl acetate(3×25 ml). The combined organic phases were washed with saturated sodiumchloride solution and dried over sodium sulfate. After evaporation, theresidue was purified by reverse phase chromatography (Waters XSelect CSHC18 column, 0-70% acetonitrile/0.1% aqueous formic acid gradient) togiveN-tert-butyl-2-[methyl(2-{4-[(2R)-oxiran-2-ylmethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(35 mg, 25%) as an off-white solid. LCMS (ES+): [M+H]⁺=412.1.

N-Tert-butyl-2-[methyl(2-{4-[(2R)-oxiran-2-ylmethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(40 mg; 0.1 mmol; 1 eq.) was suspended in toluene (5 ml).Tetrabutylammonium fluoride (0.49 mL; 1 mol/L THF; 0.49 mmol; 5 eq.) wasadded slowly. The reaction was warmed to 80° C. in a sand bath for 3 h.Solvents were evaporated and the residue was purified by reverse phasechromatography (Waters XSelect CSH C18 column, 0-60% acetonitrile/0.1%aqueous formic acid gradient) to giveN-tert-butyl-2-[(2-{4-[(2S)-3-fluoro-2-hydroxypropoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(18 mg, 43%) as a white solid. LCMS (ES+): [M+H]⁺=432.1. ¹H NMR (400MHz, DMSO-d6) δ 8.48 (d, J=5.6 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.68 (s,1H), 7.06 (dd, J=5.6, 2.6 Hz, 1H), 5.52 (s, 1H), 4.62-4.53 (m, 1H),4.50-4.41 (m, 1H), 4.15-4.04 (m, 5H), 3.26 (s, 3H), 3.16-3.11 (m, 3H),2.84-2.77 (m, 2H), 2.03-1.94 (m, 2H), 1.24 (s, 9H).

Example 1.459 Synthesis of(2R)-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(propan-2-yl)propanamide(Compound 453)

Compound 453 was synthesized similar to Compound 389 by replacingN-isopropyl-2-(methylamino)acetamide hydrochloride with(2R)—N-isopropyl-2-(methylamino)propenamide. LCMS (ES) [M+1]⁺ m/z: 428.¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (d, J=5.6 Hz, 1H), 8.27 (d, J=8.0 Hz,1H), 7.88 (d, J=2.6 Hz, 1H), 7.07 (dd, J=5.7, 2.6 Hz, 1H), 5.11 (q,J=7.0 Hz, 1H), 4.70 (s, 1H), 3.89 (s, 2H), 4-3.85 (m, 1H), 3.28-3.16 (m,1H), 3.11-3.04 (m, 4H), 2.96-2.77 (m, 2H), 2.10-1.92 (m, 2H), 1.34 (d,J=7.0 Hz, 3H), 1.24 (s, 6H), 1.09 (d, J=6.6 Hz, 3H), 0.90 (d, J=6.5 Hz,3H).

Example 1.460 Synthesis ofN-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-6,6-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 454)

Compound 454 was synthesized similar to Compound 348 by replacing methyl2-oxocyclopentane-1-carboxylate with4,4-dimethyl-2-oxocyclopentane-1-carboxylate. LCMS (ES) [M+1]⁺ m/z: 455.¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, J=5.7 Hz, 1H), 7.83 (d, J=2.6 Hz,1H), 7.65 (s, 1H), 7.05 (dd, J=5.7, 2.7 Hz, 1H), 4.20 (t, J=5.7 Hz, 2H),4.10 (s, 2H), 3.24 (s, 3H), 2.95 (s, 2H), 2.70-2.63 (m, 4H), 2.23 (s,6H), 1.25 (s, 9H), 1.15 (s, 6H).

Example 1.461 Synthesis of2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-6,6-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(propan-2-yl)acetamide(Compound 455)

Compound 455 was synthesized similar to Compound 348 by replacing methyl2-oxocyclopentane-1-carboxylate with4,4-dimethyl-2-oxocyclopentane-1-carboxylate and by replacingtert-butylamine with propan-2-amine. LCMS (ES) [M+1]⁺ m/z: 441. ¹H NMR(400 MHz, DMSO-d₆) δ 8.47 (d, J=5.5 Hz, 1H), 8.21 (s, 2HCOOH), 7.97 (d,J=7.9 Hz, 1H), 7.80 (d, J=2.6 Hz, 1H), 7.05 (dd, J=5.7, 2.6 Hz, 1H),4.20 (t, J=5.7 Hz, 2H), 4.12 (s, 2H), 3.92-3.83 (m, 1H), 3.24 (s, 3H),2.95 (s, 2H), 2.72-2.64 (m, 4H), 2.24 (s, 6H), 1.15 (s, 6H), 1.05 (d,J=6.6 Hz, 6H).

Example 1.462 Synthesis of2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-7,7-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(propan-2-yl)acetamide(Compound 456)

Compound 456 was synthesized similar to Compound 348 by replacing methyl2-oxocyclopentane-1-carboxylate with3,3-dimethyl-2-oxocyclopentane-1-carboxylate and by replacingtert-butylamine with propan-2-amine. LCMS (ES) [M+1]⁺ m/z: 441. ¹H NMR(300 MHz, DMSO-d6, ppm): δ 8.50 (d, J=5.6 Hz, 1H), 8.00 (d, J=7.8 Hz,1H), 7.81 (d, J=2.5 Hz, 1H), 7.07 (dd, J=5.7, 2.6 Hz, 1H), 4.19 (t,J=5.7 Hz, 2H), 4.14 (s, 2H), 3.87 (dq, J=13.3, 6.6 Hz, 1H), 3.28 (s,3H), 3.10 (t, J=7.0 Hz, 2H), 2.66 (t, J=5.7 Hz, 2H), 2.23 (s, 6H), 1.87(t, J=7.0 Hz, 2H), 1.22 (s, 6H), 1.05 (d, J=6.6 Hz, 6H).

Example 1.463 Synthesis ofN-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-7,7-dimethyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 457)

Compound 457 was synthesized similar to Compound 348 by replacing methyl2-oxocyclopentane-1-carboxylate with3,3-dimethyl-2-oxocyclopentane-1-carboxylate. LCMS (ES) [M+1]⁺ m/z: 441.¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.51 (d, J=5.6 Hz, 1H), 7.84 (d, J=2.5Hz, 1H), 7.69 (s, 1H), 7.08 (dd, J=5.7, 2.6 Hz, 1H), 4.22 (t, J=5.7 Hz,2H), 4.13 (s, 2H), 3.28 (s, 3H), 3.12 (t, J=7.0 Hz, 2H), 2.68 (t, J=5.7Hz, 2H), 2.23 (s, 6H), 1.89 (t, J=7.0 Hz, 2H), 1.25 (s, 9H), 1.22 (s,6H).

Example 1.464 Synthesis ofN-[(2R)-1-hydroxypropan-2-yl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamidede(Compound 458)

Compound 458 was synthesized similar to Compound 135 by replacingoxolan-3-amine with (R)-2-amino-1-propanol. LCMS (ES) [M+1]⁺ m/z: 372.¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.48 (d, J=5.6 Hz, 1H), 7.88 (d, J=8.2Hz, 1H), 7.82 (d, J=2.6 Hz, 1H), 7.04 (dd, J=5.7, 2.6 Hz, 1H), 4.65 (t,J=5.6 Hz, 1H), 4.22 (d, J=16.4 Hz, 1H), 4.15 (d, J=16.4 Hz, 1H), 3.90(s, 3H), 3.80 (p, J=6.8 Hz, 1H), 3.39-3.32 (m, 1H), 3.27 (s, 3H), 3.21(q, J=5.4, 4.6 Hz, 1H), 3.16 (q, J=7.4, 5.5 Hz, 2H), 2.82 (t, J=7.9 Hz,2H), 2.02-1.95 (m, 2H), 1.01 (d, J=6.7 Hz, 3H).

Example 1.465 Synthesis ofN-[(2S)-1-hydroxypropan-2-yl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 459)

Compound 459 was synthesized similar to Compound 135 by replacingoxolan-3-amine with (S)-2-amino-1-propanol. LCMS (ES) [M+1]⁺ m/z: 372.¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.48 (d, J=5.6 Hz, 1H), 7.88 (d, J=8.1Hz, 1H), 7.82 (d, J=2.6 Hz, 1H), 7.04 (dd, J=5.7, 2.6 Hz, 1H), 4.65 (t,J=5.6 Hz, 1H), 4.22 (d, J=16.4 Hz, 1H), 4.14 (d, J=16.4 Hz, 1H), 3.89(s, 3H), 3.78 (q, J=6.7 Hz, 1H), 3.33 (d, J=6.0 Hz, 1H), 3.26 (s, 3H),3.25-3.11 (m, 3H), 2.82 (t, J=7.8 Hz, 2H), 2.04-1.93 (m, 2H), 1.00 (d,J=6.7 Hz, 3H).

Example 1.466 Synthesis ofN-tert-butyl-2-[methyl(2-{4-[2-(morpholin-4-yl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 460)

Compound 460 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with 4-morpholineethanol. LCMS (ES) [M+1]⁺ m/z:469. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.47 (d, J=5.6 Hz, 1H), 7.84 (d,J=2.5 Hz, 1H), 7.68 (s, 1H), 7.06 (dd, J=5.7, 2.6 Hz, 1H), 4.24 (t,J=5.6 Hz, 2H), 4.13 (s, 2H), 3.59 (d, J=9.3 Hz, 4H), 3.27 (s, 3H), 3.15(t, J=7.3 Hz, 2H), 2.88-2.67 (m, 4H), 2.48 (d, J=4.5 Hz, 4H), 2.01-1.96(m, 2H), 1.25 (s, 9H).

Example 1.467 Synthesis ofN-tert-butyl-2-{methyl[2-(4-{2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 461)

Compound 461 was synthesized similar to Compound 508 by replacingbis(methyl-d3)amine hydrochloride with(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride. LCMS (ES) [M+1]⁺m/z: 481. ¹H NMR (400 MHz, DMSO-d6, ppm): δ 8.47 (d, J=5.5 Hz, 1H), 8.16(s, 2HCOOH), 7.83 (d, J=2.6 Hz, 1H), 7.66 (s, 1H), 7.05 (dd, J=5.7, 2.6Hz, 1H), 4.34 (s, 1H), 4.17 (t, J=5.7 Hz, 2H), 4.13 (s, 2H), 3.86 (d,J=7.6 Hz, 1H), 3.61-3.50 (m, 2H), 3.26 (s, 3H), 3.15 (t, J=7.3 Hz, 2H),2.97 (dq, J=11.6, 6.6, 6.2 Hz, 2H), 2.92-2.88 (m, 1H), 2.81 (t, J=7.9Hz, 2H), 2.53 (d, J=6.8 Hz, 1H), 2.00-1.96 (m, 2H), 1.74 (d, J=9.4 Hz,1H), 1.60 (d, J=9.6 Hz, 1H), 1.25 (s, 9H).

Example 1.468 Synthesis ofN-tert-butyl-2-{methyl[2-(4-{2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 462)

Compound 462 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethanol. LCMS (ES)[M+1]⁺ m/z: 481. ¹H NMR (400 MHz, DMSO-d6, ppm): δ 8.47 (d, J=5.6 Hz,1H), 8.16 (s, 2HCOOH), 7.83 (d, J=2.5 Hz, 1H), 7.67 (s, 1H), 7.05 (dd,J=5.7, 2.5 Hz, 1H), 4.35 (s, 1H), 4.22-4.10 (m, 4H), 3.86 (d, J=7.6 Hz,1H), 3.59 (s, 1H), 3.53 (dd, J=7.6, 1.8 Hz, 1H), 3.26 (s, 3H), 3.14 (t,J=7.3 Hz, 2H), 3.07-2.86 (m, 3H), 2.81 (t, J=7.8 Hz, 2H), 2.55-2.50 (m,1H), 2.02-1.96 (m, 2H), 1.75 (dd, J=9.5, 2.1 Hz, 1H), 1.60 (d, J=9.4 Hz,1H), 1.24 (s, 9H).

Example 1.469 Synthesis ofN-tert-butyl-2-{[2-(4-{2-[(3R)-3-methoxypyrrolidin-1-yl]ethoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 463)

Compound 463 was synthesized similar to Compound 508 by replacingbis(methyl-d3)amine hydrochloride with (3R)-3-methoxypyrrolidinehydrochloride. LCMS (ES) [M+1]⁺ m/z: 483. ¹H NMR (400 MHz, DMSO-d6,ppm): δ 8.48 (d, J=5.6 Hz, 1H), 8.16 (s, 2HCOOH), 7.84 (d, J=2.6 Hz,1H), 7.67 (s, 1H), 7.06 (dd, J=5.7, 2.6 Hz, 1H), 4.23 (t, J=5.6 Hz, 2H),4.13 (s, 2H), 3.95-3.85 (m, 1H), 3.27 (s, 3H), 3.18 (s, 3H), 3.14 (7J=7.3 Hz, 2H), 2.90 (t, J=5.6 Hz, 2H), 2.89-2.73 (m, 3H), 2.77- 2.52 (m,3H), 2.01-1.93 (m, 3H), 1.73-1.53 (m, 1H), 1.25 (s, 9H).

Example 1.470 Synthesis ofN-tert-butyl-2-{[2-(4-{2-[(3S)-3-methoxypyrrolidin-1-yl]ethoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 464)

Compound 464 was synthesized similar to Compound 508 by replacingbis(methyl-d3)amine hydrochloride with (3S)-3-methoxypyrrolidinehydrochloride. LCMS (ES) [M+1]⁺ m/z: 483. ¹H NMR (400 MHz, DMSO-d6,ppm): δ 8.49 (d, J=5.6 Hz, 1H), 8.15 (s, 1.5HCOOH), 7.84 (d, J=2.5 Hz,1H), 7.67 (s, 1H), 7.07 (dd, J=5.7, 2.6 Hz, 1H), 4.25 (t, J=5.6 Hz, 2H),4.14 (s, 2H), 3.94-3.89 (m, 1H), 3.26 (s, 3H), 3.18 (s, 3H), 3.14 (t,J=7.3 Hz, 2H), 2.96 (t, J=5.6 Hz, 2H), 2.89 (dd, J=10.5, 6.1 Hz, 1H),2.83-2.77 (m, 3H), 2.73 (dd, J=10.5, 3.0 Hz, 1H), 2.69-2.62 (m, 1H),2.06-1.95 (m, 3H), 1.75-1.68 (m, 1H), 1.24 (s, 9H).

Example 1.471 Synthesis ofN-tert-butyl-2-[(2-{4-[2-(1H-imidazol-1-yl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 465)

Compound 465 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with 1-(2-hydroxyethyl)imidazole. LCMS (ES) [M+1]⁺m/z: 450. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.48 (d, J=5.6 Hz, 1H), 7.82(d, J=2.6 Hz, 1H), 7.75-7.63 (m, 2H), 7.27 (t, J=1.3 Hz, 1H), 7.04 (dd,J=5.6, 2.6 Hz, 1H), 6.91 (d, J=1.1 Hz, 1H), 4.42 (s, 4H), 4.14 (s, 2H),3.26 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.01-1.96(m, 2H), 1.23 (s, 10H).

Example 1.472 Synthesis ofN-tert-butyl-2-[methyl(2-{4-[2-(1H-1,2,3,4-tetrazol-1-yl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 466)

Compound 466 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with 2-(1H-1,2,3,4-tetrazol-1-yl)ethan-1-ol. LCMS(ES) [M+1]⁺ m/z: 452.2. ¹H NMR (400 MHz, DMSO-d6, ppm): δ 9.52 (s, 1H),8.54 (d, J=5.7 Hz, 1H), 7.84 (d, J=2.6 Hz, 1H), 7.71 (s, 1H), 7.15 (dd,J=5.8, 2.6 Hz, 1H), 4.96-4.91 (m, 2H), 4.68-4.63 (m, 2H), 4.17 (s, 2H),3.29 (s, 3H), 3.17-3.12 (m, 2H), 2.88-2.81 (m, 2H), 2.04-1.96 (m, 2H),1.19 (s, 9H).

Example 1.473 Synthesis ofN-tert-butyl-2-{[2-(4-ethoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 467)

Compound 467 was synthesized similar to Compound 34 by replacing4-methoxy-2-(trimethylstannyl)pyridine with4-ethoxy-2-(tributylstannyl)pyridine. LCMS (ES+): [M+H]⁺=384.2. ¹H NMR(400 MHz, DMSO-d6) δ 8.48 (d, J=5.7 Hz, 1H), 7.86 (d, J=2.5 Hz, 1H),7.72 (s, 1H), 7.06 (dd, J=5.7, 2.6 Hz, 1H), 4.19 (q, J=7.0 Hz, 2H), 4.13(s, 2H), 3.28 (s, 3H), 3.19-3.11 (m, 2H), 2.86-2.79 (m, 2H), 2.04-1.94(m, 2H), 1.37 (t, J=7.0 Hz, 3H), 1.24 (s, 9H).

Example 1.474 Synthesis ofN-tert-butyl-2-[methyl(2-{4-[2-(pyridazin-3-yloxy)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 468)

Compound 468 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with 2-(pyridazin-3-yloxy)ethan-1-ol. LCMS (ES)[M+1]⁺ m/z: 478.2. ¹H NMR (400 MHz, DMSO-d6, ppm): δ 8.92 (dd, J=4.5,1.3 Hz, 1H), 8.50 (d, J=5.6 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.68 (s,1H), 7.65 (dd, J=8.9, 4.5 Hz, 1H), 7.26 (dd, J=8.9, 1.3 Hz, 1H), 7.12(dd, J=5.7, 2.6 Hz, 1H), 4.83-4.78 (m, 2H), 4.57-4.53 (m, 2H), 4.10 (s,2H), 3.27 (s, 3H), 3.17-3.12 (m, 2H), 2.84-2.78 (m, 2H), 2.03-1.94 (m,2H), 1.18 (s, 9H).

Example 1.475 Synthesis of2-({2-[4-(2-ethyl-2-hydroxybutoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-[(1R,2S)-2-hydroxycyclopentyl]acetamidede(Compound 469)

Step 1

Into a 20-mL vial, was placed NaH (60% in mineral oil) (68 mg, 1.71mmol, 1.50 equiv), DMSO (4.0 mL), After cooled to 0° C.,2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butan-1-ol (300 mg, 1.71 mmol,1.50 equiv) was added and stirred at room temperature and stirred for0.5 h. This was followed by2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (282mg, 1.14 mmol, 1.00 equiv) was added. The resulting solution was stirredfor 12 h at 40° C., the reaction mixture was cooled to room temperatureand quenched with H₂O (1.0 mL), the resulting solution was purified byPrep-HPLC with the following conditions: Sunfire Prep C18 OBD Column,50*250 mm, 5 μm, 10 nm, Mobile phase A, water (0.05% NH₃·H₂O) and CH₃CN(25% Phase B up to 60% in 12 min), Detector, 220 nm. 305 mg of2-(4-(2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-olwas obtained as a yellow oil. LCMS (ES) [M+1]⁺ m/z: 414.

Step 2

Into a 50-mL three necked round-bottom flask were placed2-(4-(2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol(305 mg, 0.74 mmol, 1.00 equiv), DCM (10.00 mL) and TEA (0.51 mL, 3.69mmol, 5.00 equiv). This was followed by the addition oftrifluoromethanesulfonic anhydride (0.14 ml, 0.96 mmol, 1.30 equiv) at0° C. The resulting solution was stirred for 2 h at room temperature.The reaction was quenched with H₂O (10 mL) and extracted with DCM (20mL*3). Organic layers were combined, dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated under reduced pressure, theresidue was used to the next step without further purification. Thisresulted in 763 mg crude of2-(4-(2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yltrifluoromethanesulfonate purple oil. LCMS: (ES) [M+1]⁺ m/z: 546.

Step 3

Into a 100-mL round-bottom flask were placed2-(4-(2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yltrifluoromethanesulfonate (763 mg, 1.40 mmol, 1.00 equiv) and DCM (10.0mL). This was followed by the addition of TEA (0.59 mL, 4.20 mmol, 3.00equiv) andN-((1R,2S)-2-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-2-(methylamino)acetamidehydrochloride (874 mg, 1.96 mmol, 1.40 equiv). The resulting solutionwas stirred for 12 h at 40° C. The reaction was quenched with H₂O (20mL), extracted with DCM (20 mL*2). Organic layers were combined, driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure, the residue was used to the nextstep without further purification. This resulted in 1.1 g crude ofN-((1R,2S)-2-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-2-((2-(4-(2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamidea brown oil. LCMS: (ES) [M+1]⁺ m/z: 806.

Step 4

Into a 100-mL round-bottom flask were placedN-((1R,2S)-2-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-2-((2-(4-(2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(1.10 g, 1.37 mmol, 1.00 equiv), THE (10.00 mL) and TBAF (0.37 mL, 1.37mmol, 1.00 equiv). The reaction solution was stirred for 12 h at roomtemperature. The resulting solution was concentrated under reducedpressure, the residue was purified by Prep-HPLC with the followingconditions: Welch-XB C18 50*250, 10 um, Mobile phase A, water (0.05%NH₃·H₂O) and CH₃CN (30% Phase B up to 80% in 15 min), Detector, 220 nm.268 mg of2-((2-(4-(2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-((1R,2S)-2-hydroxycyclopentyl)acetamidewas obtained as an orange solid. LCMS (ES) [M+1]⁺ m/z: 568.

Step 5

Into a 8-mL vial were placed2-((2-(4-(2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-((1R,2S)-2-hydroxycyclopentyl)acetamide(268 mg, 0.47 mmol, 1.00 equiv), MeOH (3.0 mL) and TsOH (81 mg, 0.47mmol, 1.00 equiv). The mixture was stirred for 1 h at room temperature.The reaction mixture was purified by Prep-HPLC with the followingconditions: Welch-XB C18 50*250, 10 um, Mobile phase, water (0.5%NH₃·H₂O) and CH₃CN/MeOH 1:1 (25% Phase B up to 75% in 15 min), Detector,220 nm. 130 mg of2-((2-(4-(2-ethyl-2-hydroxybutoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-((1R,2S)-2-hydroxycyclopentyl)acetamidewas obtained as a white solid. LCMS (ES, m/z): [M+H]⁺: 484. ¹H-NMR (300MHz, DMSO-d6, ppm): δ 8.48 (d, J=5.6 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H),7.68 (d, J=7.8 Hz, 1H), 7.07 (dd, J=5.6, 2.6 Hz, 1H), 4.69 (d, J=3.8 Hz,1H), 4.44 (s, 1H), 4.31 (d, J=16.6 Hz, 1H), 4.20 (d, J=16.6 Hz, 1H),3.96-3.81 (m, 4H), 3.26 (s, 3H), 3.19-3.12 (m, 2H), 2.85 (t, J=7.8 Hz,2H), 2.04-1.94 (m, 2H), 1.80-1.63 (m, 3H), 1.59-1.35 (m, 7H), 0.88 (t,J=7.4 Hz, 6H).

Example 1.476 Synthesis ofN-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(2,2,2-trifluoroethyl)amino]acetamide(Compound 470)

Step 1

To a stirred mixture of2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-ol (10 g,40.375 mmol, 1.00 equiv) and TEA (8.17 g, 80.750 mmol, 2 equiv) in DCM(200 mL) was added (trifluoromethane)sulfonyl trifluoromethanesulfonate(22.78 g, 80.750 mmol, 2 equiv) dropwise at 0° C. The resulting mixturewas stirred for 4 h at room temperature under nitrogen atmosphere. Theresulting mixture was extracted with CH₂Cl₂ (3×300 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with PE/EA (1:2) toafford 2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yltrifluoromethanesulfonate (10 g, 65.22%) as off-white solid. LCMS (ES)[M+1]⁺ m/z: 380.

Step 2

To a stirred mixture of2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yltrifluoromethanesulfonate (3 g, 7.900 mmol, 1.00 equiv) and2,2,2-trifluoroethylamine (7.83 g, 79.000 mmol, 10 equiv) in DMF wasadded K₂CO₃ (3.28 g, 23.700 mmol, 3 equiv) in portions at roomtemperature. The resulting mixture was extracted with CH₂Cl₂ (3×50 mL).The combined organic layers were dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by reverse flash chromatography with the followingconditions: column, silica gel; mobile phase, MeCN in water (0.1% NH₃),10% to 60% gradient in 20 min to afford2-(4-chloropyridin-2-yl)-N-(2,2,2-trifluoroethyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(500 mg, 19.25%) as a white solid. LCMS (ES) [M+1]⁺ m/z: 329.

Step 3

To a stirred solution of2-(4-chloropyridin-2-yl)-N-(2,2,2-trifluoroethyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine(400 mg, 1.217 mmol, 1.00 equiv) in DMF was added NaH (58.40 mg, 2.434mmol, 2 equiv) in portions at 0° C. under nitrogen atmosphere. Theresulting mixture was stirred for 30 min at 0° C. under nitrogenatmosphere. To the above mixture was added 2-bromo-N-tert-butylacetamide(354.23 mg, 1.826 mmol, 1.5 equiv) in portions at ° C. The resultingmixture was stirred for additional 4 h at room temperature. Theresulting mixture was extracted with CH₂Cl₂ (3×30 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH(10:1) to affordN-tert-butyl-2-{[2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](2,2,2-trifluoroethyl)amino}acetamide(300 mg, 55.79%) as an off-white solid. LCMS (ES) [M+1]⁺ m/z: 442.

Step 4

To a stirred solution ofN-tert-butyl-2-{[2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](2,2,2-trifluoroethyl)amino}acetamide(130 mg, 0.294 mmol, 1.00 equiv) and dimethylaminoethanol (10 mL) wasadded CuCl₂ (3.96 mg, 0.029 mmol, 0.1 equiv) and K₂CO₃ (81.32 mg, 0.588mmol, 2 equiv) in portions at 100° C. The resulting mixture wasextracted with CH₂Cl₂ (3×30 mL). The combined organic layers were driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated underreduced pressure. The crude product was purified by Prep-HPLC with thefollowing conditions (Sunfire Prep C18 XBridge Column, 19*150 mm; mobilephase A, Water (0.0.05% NH3) and mobile phase B, AcCN (25% Phase B up to72% in 7 min)) to affordN-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(2,2,2-trifluoroethyl)amino]acetamide(49.3 mg, 33.88%) as a white solid. LCMS (ES) [M+1]⁺ m/z: 495. ¹H NMR(400 MHz, DMSO-d₆) δ 8.49 (d, J=5.5 Hz, 1H), 7.83 (s, 1H), 7.68 (s, 1H),7.07 (s, 1H), 4.59 (q, J=9.2 Hz, 2H), 4.27-4.17 (m, 4H), 3.07 (t, J=7.3Hz, 2H), 2.86 (t, J=8.0 Hz, 2H), 2.67 (t, J=5.7 Hz, 2H), 2.23 (s, 6H),2.05-1.97 (m, 2H), 1.24 (s, 9H).

Example 1.477 Synthesis of1-[(3R)-3-hydroxypyrrolidin-1-yl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}ethan-1-one(Compound 471)

Compound 471 was synthesized similar to Compound 135 by replacingoxolan-3-amine with (3R)-pyrrolidin-3-ol. LCMS (ES) [M+1]⁺ m/z: 384. ¹HNMR (300 MHz, DMSO-d6, ppm): δ 8.47 (d, J=5.6 Hz, 1H), 7.74 (dd, J=4.2,2.6 Hz, 1H), 7.02 (dd, J=5.6, 2.6 Hz, 1H), 5.07 (d, J=3.4 Hz, 1H), 4.94(d, J=3.4 Hz, 1H), 4.60-4.19 (m, 3H), 3.88 (s, 3H), 3.77-3.54 (m, 2H),3.50-3.36 (m, 1H), 3.31-3.23 (m, 4H), 3.14 (t, J=7.4 Hz, 2H), 2.81 (t,J=7.9 Hz, 2H), 2.05-1.78 (m, 4H).

Example 1.478 Synthesis of1-[(3S)-3-hydroxypyrrolidin-1-yl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}ethan-1-one(Compound 472)

Compound 472 was synthesized similar to Compound 135 by replacingoxolan-3-amine with (3S)-pyrrolidin-3-ol. LCMS (ES) [M+1]⁺ m/z: 384. ¹HNMR (300 MHz, DMSO-d6, ppm): δ 8.47 (d, J=5.6 Hz, 1H), 7.74 (dd, J=4.2,2.6 Hz, 1H), 7.02 (dd, J=5.6, 2.6 Hz, 1H), 5.07 (d, J=3.5 Hz, 0.5H),4.94 (d, J=3.5 Hz, 0.5H) 4.60-4.21 (m, 3H), 3.88 (s, 3H), 3.75-3.51 (m,2H), 3.49-3.35 (m, 1H), 3.32-3.21 (m, 4H), 3.14 (t, J=7.3 Hz, 2H), 2.81(t, J=7.9 Hz, 2H), 2.12-1.67 (m, 4H).

Example 1.479 Synthesis ofN-tert-butyl-2-{[2-(4-{2-[(3R)-3-fluoropyrrolidin-1-yl]ethoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 473)

Compound 473 was synthesized similar to Compound 508 by replacingbis(methyl-d3)amine hydrochloride with (3R)-3-fluoropyrrolidinehydrochloride. LCMS (ES) [M+1]⁺ m/z: 471. ¹H NMR (400 MHz, DMSO-d₆) δ8.48 (d, J=5.5 Hz, 1H), 7.84 (d, J=2.5 Hz, 1H), 7.67 (s, 1H), 7.06 (dd,J=5.7, 2.6 Hz, 1H), 5.20 (dt, J=55.6, 5.8 Hz, 1H), 4.23 (t, J=5.6 Hz,2H), 4.13 (s, 2H), 3.27 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.99-2.77 (m,6H), 2.79-2.63 (m, 1H), 2.43 (q, J=8.0 Hz, 1H), 2.23-2.05 (m, 1H),2.04-1.78 (m, 3H), 1.25 (s, 9H).

Example 1.480 Synthesis ofN-tert-butyl-2-{[2-(4-{2-[(3S)-3-fluoropyrrolidin-1-yl]ethoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 474)

Compound 474 was synthesized similar to Compound 508 by replacingbis(methyl-d3)amine hydrochloride with (3S)-3-fluoropyrrolidinehydrochloride. LCMS (ES) [M+1]⁺ m/z: 471. ¹H NMR (400 MHz, DMSO-d₆) δ8.48 (d, J=5.4 Hz, 1H), 8.16 (s, 1.3 HCOOH) 7.84 (d, J=2.7 Hz, 1H), 7.67(s, 1H), 7.06 (dd, J=5.9, 2.7 Hz, 1H), 5.20 (dt, J=55.8, 5.8 Hz, 1H),4.23 (t, J=5.7 Hz, 2H), 4.13 (s, 2H), 3.27 (s, 3H), 3.15 (t, J=7.4 Hz,2H), 3.00-2.77 (m, 6H), 2.79-2.63 (m, 1H), 2.43 (q, J=7.9 Hz, 1H),2.23-2.04 (m, 1H), 2.04-1.79 (m, 3H), 1.25 (s, 9H).

Example 1.481 Synthesis ofN-tert-butyl-2-[(2-{4-[3-(dimethylamino)propyl]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 475)

Step 1

Into a 40 mL vial were addedN-tert-butyl-2-{[2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(415 mg, 1.11 mmol, 1.00 equiv), dimethyl(prop-2-yn-1-yl)amine (185 mg,2.23 mmol, 2.00 equiv), DMF (10 mL), CuI (21 mg, 0.11 mmol, 0.10 equiv),Et₃N (337 mg, 3.33 mmol, 3.00 equiv) and Pd(PPh₃)Cl₂ (79 mg, 0.11 mmol,0.10 equiv) at room temperature. The resulting mixture was stirred for 3h at 100° C. under nitrogen atmosphere. The reaction was cooled to roomtemperature, the residue was purified by reverse flash chromatographywith the following conditions: C18-120 g column, mobile phase, Phase B,MeCN, Phase A, water, 10% to 50% gradient in 10 min, detector, UV 254nm. This resulted inN-(tert-butyl)-2-((2-(4-(3-(dimethylamino)prop-1-yn-1-yl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(140 mg, 30%) as a white solid. LCMS (ES, m/z): [M+H]⁺: 421.

Step 2

To a solution ofN-tert-butyl-2-[(2-{4-[3-(dimethylamino)prop-1-yn-1-yl]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(140 mg, 0.33 mmol, 1.00 equiv) in 20 mL MeOH was added Pd/C (10%, 50mg), Pd(OH)₂/C (50 mg) under hydrogen atmosphere in a 50 mL pressuretank reactor. The mixture was hydrogenated at room temperature for 1 hunder hydrogen atmosphere, filtered through a celite pad and thefiltrate was concentrated under reduced pressure. The crude product waspurified by Prep-HPLC with the following conditions: Sunfire Prep C18OBD Column, 50*250 mm, 5 μm 10 nm, mobile phase, water (0.1% FA) andCH₃CN (hold 5% Phase B in 3 min, up to 23% in 12 min), Detector, UV 254nm. This resulted inN-(tert-butyl)-2-((2-(4-(3-(dimethylamino)propyl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(74.8 mg, 43%) as a brown solid. LCMS (ES, m/z): [M+H]⁺: 425. ¹H-NMR(300 MHz, DMSO-d₆) δ 8.55 (d, J=4.9 Hz, 1H), 8.23 (s, 2HCOOH), 8.15 (d,J=1.5 Hz, 1H), 7.69 (s, 1H), 7.31 (dd, J=4.9, 1.7 Hz, 1H), 4.16 (s, 2H),3.27 (s, 3H), 3.15 (t, J=7.2 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.76-2.65(m, 2H), 2.48-2.37 (m, 2H), 2.28 (s, 6H), 2.07-1.91 (m, 2H), 1.82 (p,J=7.6 Hz, 2H), 1.24 (s, 9H).

Example 1.482 Synthesis ofN-[2-(dimethylamino)ethyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 476)

Compound 476 was synthesized similar to Compound 135 by replacingoxolan-3-amine with (2-aminoethyl)dimethylamine. LCMS (ES) [M+1]⁺ m/z:385. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.48 (d, J=5.6 Hz, 1H), 8.06 (t,J=5.8 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H), 7.04 (dd, J=5.6, 2.6 Hz, 1H),4.18 (s, 2H), 3.90 (s, 3H), 3.27 (s, 3H), 3.17 (dq, J=8.2, 5.6, 4.1 Hz,4H), 2.82 (t, J=7.8 Hz, 2H), 2.23 (t, J=6.8 Hz, 2H), 2.07 (s, 6H),2.02-1.94 (m, 2H).

Example 1.483 Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-1-(morpholin-4-yl)ethan-1-one(Compound 477)

Compound 477 was synthesized similar to Compound 135 by replacingoxolan-3-amine with morpholine. LCMS (ES) [M+1]⁺ m/z: 384. ¹H NMR (300MHz, DMSO-d6, ppm): δ 8.49 (d, J=5.6 Hz, 1H), 7.78 (d, J=2.6 Hz, 1H),7.06 (dd, J=5.7, 2.6 Hz, 1H), 4.55 (s, 2H), 3.90 (s, 3H), 3.67-3.65 (m,2H), 3.58-3.53 (m, 4H), 3.45-3.43 (m, 2H), 3.28 (s, 3H), 3.15 (t, J=7.4Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.00 (p, J=7.8 Hz, 2H).

Example 1.484 Synthesis of2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(2,2,2-trifluoroethyl)acetamide(Compound 478)

Compound 478 was synthesized similar to Compound 348 by replacingtert-butylamine with trifluoroethaylamine. LCMS (ES+): [M+H]⁺=453.1. ¹HNMR (400 MHz, dmso) δ 8.93 (t, J=6.4 Hz, 1H), 8.46 (d, J=5.6 Hz, 1H),7.77 (d, J=2.5 Hz, 1H), 7.04 (dd, J=5.7, 2.6 Hz, 1H), 4.28 (s, 2H), 4.22(t, J=5.6 Hz, 2H), 3.92 (qd, J=9.8, 6.3 Hz, 2H), 3.29 (s, 3H), 3.19-3.12(m, 2H), 2.86-2.79 (m, 2H), 2.75 (t, J=5.6 Hz, 2H), 2.29 (s, 6H),2.04-1.94 (m, 2H).

Example 1.485 Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(2,2,2-trifluoroethyl)acetamide(Compound 479)

Compound 479 was synthesized similar to Compound 389 by replacingtertbutylamine with trifluoroethylamine. LCMS (ES+): [M+H]⁺=454.1. ¹HNMR (400 MHz, dmso) S 8.97 (t, J=6.4 Hz, 1H), 8.45 (d, J=5.7 Hz, 1H),7.77 (d, J=2.5 Hz, 1H), 7.04 (dd, J=5.6, 2.6 Hz, 1H), 4.77-4.62 (m, 1H),4.28 (s, 2H), 3.92 (qd, J=9.7, 6.3 Hz, 2H), 3.86 (s, 2H), 3.29 (s, 3H),3.17-3.10 (m, 2H), 2.86-2.77 (m, 2H), 2.03-1.94 (m, 2H), 1.22 (s, 6H).

Example 1.486 Synthesis ofN-tert-butyl-2-[methyl(2-{4-[3-(methylamino)propyl]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 480)

Step 1

Into a 100 mL round-bottom flask were placed tert-butyl(3-hydroxypropyl)(methyl)carbamate (2.00 g, 10.60 mmol, 1.00 equiv), DCM(20.00 mL) and PPh₃ (3.67 g, 13.80 mmol, 1.30 equiv). This was followedby addition of CBr₄ (5.20 g, 13.80 mmol, 1.30 equiv) at 0° C. Theresulting solution was stirred for 1.5 h at 0° C. The reaction mixturewas quenched with H₂O (50.00 mL), extracted with DCM (100 mL*2). Thecombined organic phase was washed with Na₂CO₃ (aq), brine and dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column with petroleum ether/ethyl acetate (93%/7%). This resulted in2.6 g of tert-butyl (3-bromopropyl)(methyl)carbamate as light yellowoil.

Step 2

Into a 40-mL vial purged and maintained with an inert atmosphere ofhydrogen were placed DMAC (10 mL), picolinimidamide hydrochloride (14mg, 0.09 mmol, 0.05 equiv), NiI₂ (28 mg, 0.09 mmol, 0.05 equiv), sodiumiodide (71 mg, 0.47 mmol, 0.25 equiv), tert-butyl(3-bromopropyl)(methyl)carbamate (577 mg, 2.30 mmol, 1.20 equiv),N-(tert-butyl)-2-((2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(700 mg, 1.88 mmol, 1.00 equiv), zinc metal powder (246 mg, 3.76 mmol,2.00 equiv), and trifluoroacetic acid (22 mg, 0.19 mmol, 0.10 equiv).The reaction mixture was heated to 60° C. and stirred for 12 h. Thereaction mixture was purified by Prep-HPLC with the followingconditions: Welch-XB C18 50*250, 10 um, Mobile phase A, water (0.1% TFA)and CH₃CN (13% Phase B up to 47% in 12 min), Detector, 220 nm. Thisresulted in 252 mg of tert-butyl(3-(2-(4-((2-(tert-butylamino)-2-oxoethyl)(methyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyridin-4-yl)propyl)(methyl)carbamateas a light yellow oil. LCMS: (ES) [M+1]⁺ m/z: 511.

Step 3

Into a 20-mL vial were placed tert-butyl(3-(2-(4-((2-(tert-butylamino)-2-oxoethyl)(methyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyridin-4-yl)propyl)(methyl)carbamate(252 mg, 0.79 mmol, 1.00 equiv), HCl (g)/MeOH (4 M) (0.78 mL), DCM (3mL). The mixture was stirred for 12 h at room temperature. The reactionmixture was purified by Prep-HPLC with the following conditions: SunfirePrep C18 OBD Column, 50*250 mm, 5 μm, 10 nm, Mobile phase, water (0.1%FA) and CH₃CN (5% Phase B up to 25% in 12 min), Detector, 220 nm. 169 mgofN-(tert-butyl)-2-(methyl(2-(4-(3-(methylamino)propyl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamidewas obtained as off white solid. LCMS (ES, m/z): [M+H]⁺: 411. ¹H NMR(300 MHz, DMSO-d6, ppm): δ 8.58 (d, J=4.9 Hz, 1H), 8.30 (s, 1.4 HCOOH),8.17 (s, 1H), 7.76 (s, 1H), 7.33 (dd, J=4.9, 1.7 Hz, 1H), 4.17 (s, 2H),3.26 (s, 3H), 3.17 (t, J=7.3 Hz, 2H), 2.84-2.73 (m, 6H), 2.49 (s, 3H),2.04-1.88 (m, 4H), 1.24 (s, 9H).

Example 1.487 Synthesis ofN-tert-butyl-2-({2-[4-(3-hydroxy-3-methylbutyl)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 481)

Compound 481 was synthesized similar to Compound 475 by replacingdimethyl(prop-2-yn-1-yl)amine with 2-methyl-3-butyn-2-ol. LCMS (ES)[M+1]⁺ m/z: 426. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.53 (d, J=4.9 Hz,1H), 8.16 (s, 0.7HCOOH), 8.14 (d, J=1.7 Hz, 1H), 7.69 (s, 1H), 7.28 (dd,J=5.0, 1.7 Hz, 1H), 4.16 (s, 2H), 3.27 (s, 3H), 3.15 (t, J=7.3 Hz, 2H),2.82 (t, J=7.8 Hz, 2H), 2.76-2.67 (m, 2H), 2.07-1.91 (m, 2H), 1.75-1.64(m, 2H), 1.24 (s, 9H), 1.17 (s, 6H).

Example 1.488 Synthesis ofN-tert-butyl-2-{[2-(4-hydroxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 482)

Into a 20 mL vial were addedN-tert-butyl-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(200 mg, 0.54 mmol, 1.00 equiv) and THF (5 mL). To the above mixture wasadded L-selectride (1.62 mL, 1.62 mmol, 3.00 equiv) dropwise undernitrogen atmosphere. The resulting mixture was stirred for additional 3h at 60° C. The mixture was cooled down to room temperature. Thereaction was quenched with water (5 mL), concentrated under vacuum toremove the solvent, the residue was purified by Prep-HPLC with thefollowing conditions: Sunfire Prep C18 OBD Column, 50*250 mm, 5 μm, 10nm, mobile phase, water (0.05% NH₃H₂O) and CH₃CN (10% up to 70% in 15min) to affordN-tert-butyl-2-{[2-(4-hydroxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(49.5 mg, 26%) as an off-white solid. LCMS (ES, m/z): [M+H]⁺: 356.¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 7.71 (s, 1H), 7.64 (d, J=7.4 Hz, 1H),7.10 (s, 1H), 6.14 (d, J=7.4 Hz, 1H), 4.13 (s, 2H), 3.30 (s, 3H), 3.16(t, J=7.3 Hz, 2H), 2.84 (t, J=7.8 Hz, 2H), 2.02-1.97 (m, 2H), 1.24 (s,9H).

Example 1.489 Synthesis of2-({2-[4-(2-aminoethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-tert-butylacetamide(Compound 483)

Compound 483 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with ethanolamine. LCMS (ES) [M+1]⁺ m/z: 399. ¹HNMR (300 MHz, DMSO-d6, ppm): δ 8.75 (d, J=6.0 Hz, 1H), 8.20 (br, 3H),8.04 (d, J=2.6 Hz, 1H), 7.88 (s, 1H), 7.47 (dd, J=6.1, 2.6 Hz, 1H), 4.49(t, J=5.1 Hz, 2H), 4.38 (s, 2H), 3.42 (s, 3H), 3.33 (q, J=5.5 Hz, 2H),3.20 (s, 2H), 3.02 (t, J=7.9 Hz, 2H), 2.18-2.00 (m, 2H), 1.26 (s, 9H).

Example 1.490 Synthesis ofN-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 484)

Compound 484 was synthesized similar to Compound 348 by replacingN-(tert-butyl)-2-(methylamino)acetamide hydrochloride with2-amino-N-tert-butylacetamide hydrochloride. LCMS (ES) [M+1]⁺ m/z: 413.¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.46 (d, J=5.6 Hz, 1H), 7.86 (d, J=2.6Hz, 1H), 7.69 (s, 1H), 7.14 (t, J=5.8 Hz, 1H), 7.04 (dd, J=5.7, 2.6 Hz,1H), 4.19 (t, J=5.6 Hz, 2H), 3.93 (d, J=5.7 Hz, 2H), 2.83 (t, J=7.7 Hz,2H), 2.78-2.70 (m, 2H), 2.66 (t, J=5.6 Hz, 2H), 2.23 (s, 6H), 2.14-1.98(m, 2H), 1.25 (s, 9H).

Example 1.491 Synthesis ofN-tert-butyl-2-[(2-{4-[2-(methylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 485)

Compound 485 was synthesized similar to Compound 348 by replacingN-(tert-butyl)-2-(methylamino)acetamide hydrochloride with2-amino-N-tert-butylacetamide hydrochloride and by replacingdimethylaminoethanol with methylethanolamine. LCMS (ES) [M+1]⁺ m/z: 399.¹H NMR (300 MHz, DMSO-d6, ppm): δ 9.23 (br, 2H), 8.69 (d, J=5.9 Hz, 1H),8.41 (br, 1H), 8.08 (d, J=2.6 Hz, 1H), 7.95 (s, 1H), 7.38 (dd, J=6.2,2.5 Hz, 1H), 4.56 (t, J=5.0 Hz, 2H), 4.16 (d, J=5.8 Hz, 2H), 2.99 (t,J=7.5 Hz, 2H), 2.81 (t, J=7.4 Hz, 2H), 2.65 (s, 3H), 2.19-2.09 (m, 2H),1.25 (s, 9H).

Example 1.492 Synthesis of2-{[2-(4-{[(2R)-1-(dimethylamino)propan-2-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-[1-(trifluoromethyl)cyclopropyl]acetamide(Compound 486)

Compound 486 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with (2R)-1-(dimethylamino)propan-2-ol and byreplacing tert-butylamine with 1-(trifluoromethyl)cyclopropan-1-amine.LCMS (ES) [M+1]⁺ m/z: 493. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 9.02 (s,1H), 8.45 (dd, J=5.7, 1.7 Hz, 1H), 8.17 (s, 1.7HCOOH), 7.73 (t, J=2.2Hz, 1H), 7.13-7.03 (m, 1H), 4.86-4.80 (m, J=7.9 Hz, 1H), 4.16 (s, 2H),3.28 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.70-2.59(m, 1H), 2.52-2.49 (m, 1H), 2.27 (s, 6H), 2.04-1.94 (m, 2H), 1.29 (dd,J=6.1, 1.6 Hz, 3H), 1.22-1.15 (m, 2H), 1.03-0.95 (m, 2H).

Example 1.493 Synthesis of2-{methyl[2-(4-{[(3R)-1-methylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-[1-(trifluoromethyl)cyclopropyl]acetamide(Compound 487)

Compound 487 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with (3R)-1-methylpyrrolidin-3-ol and by replacingtert-butylamine with 1-(trifluoromethyl)cyclopropan-1-amine. LCMS (ES)[M+1]⁺ m/z: 491. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 9.02 (s, 1H), 8.45(d, J=5.6 Hz, 1H), 8.17 (s, 1HCOOH), 7.68 (d, J=2.5 Hz, 1H), 6.99 (dd,J=5.6, 2.5 Hz, 1H), 5.09-5.00 (m, 1H), 4.18 (s, 2H), 3.28 (s, 3H), 3.15(t, J=7.3 Hz, 2H), 2.82 (t, J=8.0 Hz, 3H), 2.76-2.63 (m, 2H), 2.42-2.31(m, 2H), 2.29 (s, 3H), 2.06-1.93 (m, 2H), 1.86-1.75 (m, 1H), 1.24-1.13(m, 2H), 1.03-0.94 (m, 2H).

Example 1.494 Synthesis ofN-tert-butyl-2-{[2-(4-{[(3R,5R)-1,5-dimethylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 488)

Compound 488 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with (3R,5R)-1,5-dimethylpyrrolidin-3-ol. LCMS (ES)[M+1]⁺ m/z: 453. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.45 (d, J=5.6 Hz,1H), 7.81 (d, J=2.5 Hz, 1H), 7.70 (s, 1H), 6.99 (dd, J=5.7, 2.5 Hz, 1H),5.02-4.96 (m, 1H), 4.11 (s, 2H), 3.62 (dd, J=10.2, 6.6 Hz, 1H), 3.27 (s,3H), 3.15 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.9 Hz, 2H), 2.41 (dt, J=11.4,6.0 Hz, 1H), 2.28-2.24 (m, 1H), 2.24 (s, 3H), 2.05-1.91 (m, 3H),1.91-1.78 (m, 1H), 1.26 (s, 9H), 1.06 (d, J=5.9 Hz, 3H).

Example 1.495 Synthesis ofN-tert-butyl-2-{methyl[2-(4-{[(3R)-1-methylpiperidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 489)

Compound 489 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with (3R)-1-methylpiperidin-3-ol. LCMS (ES) [M+1]⁺m/z: 453. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.47 (d, J=5.7 Hz, 1H), 8.18(s, 1.7 HCOOH), 7.84 (d, J=2.5 Hz, 1H), 7.71 (s, 1H), 7.09 (dd, J=5.7,2.6 Hz, 1H), 4.66 (dt, J=8.0, 4.1 Hz, 1H), 4.11 (s, 2H), 3.27 (s, 3H),3.14 (t, J=7.3 Hz, 2H), 2.93 (dd, J=10.6, 3.4 Hz, 1H), 2.81 (t, J=7.8Hz, 2H), 2.66-2.51 (m, 1H), 2.28 (s, 3H), 2.36-2.16 (m, 2H), 2.05-1.92(m, 3H), 1.84-1.71 (m, 1H), 1.69-1.55 (m, 1H), 1.52-1.38 (m, 1H), 1.25(s, 9H).

Example 1.496 Synthesis ofN-tert-butyl-2-{methyl[2-(4-{[(3S)-1-methylpiperidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(Compound 490)

Compound 490 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with (3S)-1-methylpiperidin-3-ol. LCMS (ES) [M+1]⁺m/z: 453. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.47 (d, J=5.7 Hz, 1H), 8.18(s, 1.7 HCOOH), 7.84 (d, J=2.5 Hz, 1H), 7.71 (s, 1H), 7.09 (dd, J=5.7,2.6 Hz, 1H), 4.66 (dt, J=8.0, 4.1 Hz, 1H), 4.11 (s, 2H), 3.27 (s, 3H),3.14 (t, J=7.3 Hz, 2H), 2.93 (dd, J=10.6, 3.4 Hz, 1H), 2.81 (t, J=7.8Hz, 2H), 2.66-2.51 (m, 1H), 2.28 (s, 3H), 2.36-2.16 (m, 2H), 2.05-1.92(m, 3H), 1.84-1.71 (m, 1H), 1.69-1.55 (m, 1H), 1.52-1.38 (m, 1H), 1.25(s, 9H).

Example 1.497 Synthesis ofN-tert-butyl-2-{[2-(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 491)

Compound 491 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with (3R)-1-(2,2-difluoroethyl)pyrrolidin-3-ol.LCMS (ES) [M+1]⁺ m/z: 489. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.46 (d,J=5.6 Hz, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.69 (s, 1H), 7.00 (dd, J=5.7,2.6 Hz, 1H), 6.12 (tt, J=55.8, 4.2 Hz, 1H), 5.06 (dt, J=7.1, 3.3 Hz,1H), 4.12 (s, 2H), 3.27 (s, 3H), 3.14 (t, J=7.3 Hz, 2H), 3.02 (dd,J=10.7, 6.0 Hz, 1H), 2.95-2.74 (m, 6H), 2.65-2.55 (m, 1H), 2.34 (dt,J=13.6, 6.9 Hz, 1H), 2.02-1.95 (m, 2H), 1.88-1.70 (m, 1H), 1.25 (s, 9H).

Example 1.498 Synthesis ofN-tert-butyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5-oxo-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 492)

To a stirred solution ofN-tert-butyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(400 mg, 0.94 mmol, 1.00 equiv) in HOAc (1.5 mL) and H₂SO₄ (0.3 mL) wereadded CrO₃ (196 mg, 1.96 mmol, 2.0 equiv) in HOAc (2.0 mL) and H₂O (0.4mL) dropwise below 10° C. under air atmosphere. The resulting mixturewas stirred for 16 h at room temperature. The mixture was basified topH-13 with (3 N) NaOH in H₂O, extracted with CH₂Cl₂/MeOH=10:1 (3*30 mL).The combined organic layers were washed with brine (1*30 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by Prep-HPLC with thefollowing conditions: C18 OBD Column, 50*250 mm, 5 μm, 10 nm, mobilephase, CH₃CN/H₂O (FA: 0.1%), from 5% to 35% in 12 min, Flow rate, 80mL/min, Detector, UV 254 nm. This result inN-tert-butyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5-oxo-6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(65 mg, 16%) as a white solid. LCMS (ES, m/z): [M+H]⁺: 442. ¹H-NMR (300MHz, DMSO-d₆, ppm): δ 8.55 (d, J=5.6 Hz, 1H), 7.92 (d, J=2.5 Hz, 1H),7.74 (s, 1H), 7.15 (dd, J=5.6, 2.6 Hz, 1H), 4.72 (s, 1H), 4.42 (s, 2H),3.89 (s, 2H), 3.34 (s, 3H), 3.12-2.97 (m, 2H), 2.69-2.58 (m, 2H), 1.25(s, 6H), 1.23 (s, 9H).

Example 1.499 Synthesis ofN-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5-hydroxy-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 493)

Step 1

To a stirred mixture ofN-tert-butyl-2-{[2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(1.0 g, 2.67 mmol, 1.00 equiv) in t-BuOH (10.0 mL) and H₂O (2.0 mL) wasadded MgSO₄ (0.97 g, 8.02 mmol, 3.00 equiv) and KMnO₄ (850 mg, 5.35mmol, 2.00 equiv) in portions at 0° C. The resulting solution wasstirred for 16 h at room temperature, filtered and concentrated, theresidue was purified by Prep-HPLC with the following conditions: SunfirePrep C18 OBD Column, 50*250 mm, 5 μm, 10 nm, mobile phase, water (0.1%FA) and CH₃CN (15% up to 50% in 12 min), Detector, UV 220 nm to affordN-tert-butyl-2-{[2-(4-chloropyridin-2-yl)-5-oxo-6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(350 mg, 33.7%) as a yellow solid. LCMS (ES) [M+1]⁺ m/z: 388.

Step 2

To a stirred solution ofN-tert-butyl-2-{[2-(4-chloropyridin-2-yl)-5-oxo-6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(300 mg, 0.77 mmol, 1.00 equiv) in MeOH (10 mL) was added NaBH₄ (58 mg,1.54 mmol, 2.00 equiv) in portions at 0° C. under N₂ atmosphere. Theresulting solution was stirred for 1 h at the same temperature. Thereaction was then quenched by the addition of water/ice (10 mL),extracted with EtOAc (30 mL*5). The combined organic layers were washedwith brine (10 mL), dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. This resulted inN-tert-butyl-2-{[2-(4-chloropyridin-2-yl)-5-hydroxy-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (286 mg, 95%) as a yellow solid used to the nextstep directly without further purification. LCMS (ES) [M+1]⁺ m/z: 390.

Step 3

To a stirred solution ofN-tert-butyl-2-{[2-(4-chloropyridin-2-yl)-5-hydroxy-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(300 mg, 0.76 mmol, 1.00 equiv) in DMF (8 mL) was added imidazole (157mg, 2.31 mmol, 3.00 equiv) and TBSCl (232 mg, 1.53 mmol, 2.00 equiv) inportions at room temperature. The reaction was stirred at 60° C. for 16h. The reaction was quenched with water (10 mL) at room temperature,extracted with EtOAc (3*30 mL). The combined organic layers were washedwith brine (20 mL*1), dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with THF/PE (1:100to 1:1) to affordN-tert-butyl-2-({5-[(tert-butyldimethylsilyl)oxy]-2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(370 mg, 95%) as an off-white solid. LCMS (ES) [M+1]⁺ m/z: 504.

Step 4

To a solution of dimethylaminoethanol (124 mg, 1.39 mmol, 2.00 equiv) inDMSO (5.0 mL) was added sodium hydride (60% in mineral oil, 55 mg, 1.39mmol, 2.00 equiv) at 15° C. After the reaction was stirred at 15˜25° C.for 1 h,N-tert-butyl-2-({5-[(tert-butyldimethylsilyl)oxy]-2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(350 mg, 0.69 mmol, 1.00 equiv) was added in one portion. Then theresulting mixture was stirred for another 2 h at 40° C. The reaction wascooled to room temperature and purified by Prep_HPLC with conditions:Kinetex EVO C18 Column, 21.2*150, 5 um, mobile phase A, water (0.1% FA)and mobile phase B, CH₃CN (10% Phase B up to 50% in 15 min), Detector,UV 254 nm, to giveN-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5-hydroxy-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(72 mg, 23.43%) as an off white solid. LCMS (ES) [M+1]⁺ m/z: 443. ¹H NMR(400 MHz, DMSO-d₆) δ 8.48 (d, J=5.6 Hz, 1H), 7.84 (d, J=2.5 Hz, 1H),7.68 (s, 1H), 7.07 (dd, J=5.7, 2.5 Hz, 1H), 5.32 (d, J=7.1 Hz, 1H),5.27-5.20 (m, 1H), 4.34-4.09 (m, 4H), 3.36 (s, 3H), 3.04 (dt, J=16.9,8.4 Hz, 1H), 2.66 (t, J=5.6 Hz, 3H), 2.23 (s, 6H), 2.25-2.15 (m, 1H),1.93 (dd, J=13.6, 8.2 Hz, 1H), 1.25 (s, 9H).

Example 1.500 Synthesis ofN-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-7-hydroxy-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 494)

Step 1

Into a 250 mL round-bottom flask were added2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (6.0 g, 31.74 mmol, 1.00equiv), HOAc (60 mL) and Pb(OAc)₄ (28.2 g, 63.60 mmol, 2.00 equiv) atroom temperature. The mixture was heated to 120° C. and stirred for 16h. Another batch Pb(OAc)₄ (28.2 g, 63.60 mmol, 2.00 equiv) was added atroom temperature and stirred for 16 h at 120° C. The reaction was cooledto room temperature and concentrated under reduced pressure to removethe solvent. The residue was purified by reverse flash chromatographywith the following conditions: column, C18-120 g, mobile phase, MeCN inwater, 10% to 50% gradient in 10 min, detector, UV 254 nm. The fractionof the target was freezing dried, this resulted in2,4-dihydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (1.4 g,21%) as a brown solid. LCMS (ES) [M+1]⁺ m/z: 211.

Step 2

Into a 250 mL round-bottom flask were added2,4-dihydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (1.4 g,6.66 mmol, 1.00 equiv), DCE (20 mL), TEA (1.35 g, 13.34 mmol, 2.00equiv) and POCl₃ (20.4 g, 133.04 mmol, 20.00 equiv) at room temperature.The resulting mixture was stirred for 2 h at 90° C. The resultingmixture was concentrated under reduced pressure. The residue was dilutedwith DCM (100 mL), quenched with water (50 mL), extracted with CH₂Cl₂(50 mL*1), dried over anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography, eluted with PE/EA (3:1) toafford 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate(1.3 g, 79%) as a yellow oil. LCMS (ES) [M+1]⁺ m/z: 247.

Step 3

Into a 40 mL vial were added2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (1.3 g,5.26 mmol, 1.00 equiv), NMP (15 mL), DIEA (2.04 g, 15.78 mmol, 3.00equiv) and N-tert-butyl-2-(methylamino)acetamide hydrochloride (1.43 g,7.92 mmol, 1.50 equiv) at room temperature. The resulting mixture wasstirred for 2 h at 60° C. The reaction was cooled to room temperature,quenched with water (20 mL), the aqueous layer was extracted with EtOAc(30 mL*3). The combined organic phase was washed with brine (20 mL*3),dried over anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with PE/EA (1:1) to afford4-((2-(tert-butylamino)-2-oxoethyl)(methyl)amino)-2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (1.5 g, 80%) as a yellow solid. LCMS (ES) [M+1]⁺ m/z: 355.

Step 4

Into a 50 mL round-bottom flask were added4-((2-(tert-butylamino)-2-oxoethyl)(methyl)amino)-2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (1.5 g, 4.23 mmol, 1.00 equiv), THE (18 mL), LiOH (0.20 g, 8.45mmol, 2.00 equiv) and H₂O (9 mL) at room temperature. The resultingmixture was stirred for 1 h at room temperature. The reaction wasdiluted with water (30 mL), extracted with EtOAc (30 mL*2). The combinedorganic phase was dried over anhydrous sodium, filtered and the filtratewas concentrated under reduced pressure. The crude product was used tothe next step directly without further purification. LCMS (ES) [M+1]⁺m/z: 313.

Step 5

Into a 50 mL round-bottom flask were addedN-(tert-butyl)-2-((2-chloro-7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(1.2 g, 3.84 mmol, 1.00 equiv), DCM (15 mL), imidazole (0.52 g, 7.67mmol, 2.00 equiv) and TBSCl (0.69 g, 4.60 mmol, 1.20 equiv) at roomtemperature. The resulting mixture was stirred for 12 h at roomtemperature. The reaction was quenched with water (30 mL), the aqueouslayer was extracted with EtOAc (50 mL*2). The residue was purified bysilica gel column chromatography, eluted with PE/EA (10:1) to affordN-(tert-butyl)-2-((7-((tert-butyldimethylsilyl)oxy)-2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(1.3 g, 79%) as a white solid. LCMS (ES) [M+1]⁺ m/z: 427.

Step 6

Into a 40 mL vial were addedN-(tert-butyl)-2-((7-((tert-butyldimethylsilyl)oxy)-2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(1.3 g, 3.05 mmol, 1.00 equiv), toluene (20 mL),4-fluoro-2-(tributylstannyl)pyridine (1.88 g, 4.87 mmol, 1.60 equiv) andPd(PPh₃)₄ (350 mg, 0.30 mmol, 0.10 equiv) at room temperature. Theresulting mixture was stirred for 12 h at 120° C. under nitrogenatmosphere. The reaction was cooled to room temperature, concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography, eluted with ethyl acetate to affordN-(tert-butyl)-2-((7-((tert-butyldimethylsilyl)oxy)-2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(900 mg, 61%) as a yellow solid. LCMS (ES) [M+1]⁺ m/z: 488.

Step 7

Into a 20 mL vial were added dimethylaminoethanol (158 mg, 1.77 mmol,2.00 equiv), DMSO (7 mL), NaH (60% in mineral oil) (71 mg, 1.78 mmol,2.00 equiv). The resulting mixture was stirred for 30 min at roomtemperature. To the above mixture was addedN-tert-butyl-2-({7-[(tert-butyldimethylsilyl)oxy]-2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(432 mg, 0.89 mmol, 1.00 equiv) at room temperature. The resultingmixture was stirred for additional 4 h at room temperature. The reactionwas quenched with water (0.5 mL) and purified by Prep-HPLC with thefollowing conditions: XBridge Shield RP18 OBD Column, 19*150 mm, 5 μm,mobile phase, water (0.05% NH₃·H₂O) and CH₃CN (16% up to 33% in 8 min).This resulted inN-(tert-butyl)-2-((2-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(57 mg, 14.54%) as an off-white solid. LCMS (ES, m/z): [M+H]⁺: 443.¹H-NMR (300 MHz, DMSO-d₆) δ 8.48 (d, J=5.6 Hz, 1H), 7.87 (d, J=2.6 Hz,1H), 7.70 (s, 1H), 7.07 (dd, J=5.7, 2.6 Hz, 1H), 5.44 (s, 1H), 4.82 (t,J=6.5 Hz, 1H), 4.20 (t, J=5.7 Hz, 2H), 4.14 (s, 2H), 3.29 (s, 3H), 3.18(ddd, J=13.8, 8.4, 4.4 Hz, 1H), 2.99 (dt, J=15.1, 7.1 Hz, 1H), 2.67 (t,J=5.6 Hz, 2H), 2.28 (dt, J=7.5, 4.9 Hz, 1H), 2.23 (s, 6H), 1.77 (dt,J=13.6, 6.8 Hz, 1H), 1.25 (s, 9H).

Example 1.501 Synthesis ofN-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[b]pyridin-4-yl)(methyl)amino]acetamide(Compound 495)

Step 1

Into a 50 mL round-bottom flask were added2,4-dichloro-5H,6H,7H-cyclopenta[b]pyridine (500.00 mg, 2.66 mmol, 1.00equiv), 4-fluoro-2-(tributylstannyl)pyridine (1129.37 mg, 2.93 mmol,1.10 equiv), DMF (25.00 mL), CsF (807.78 mg, 5.32 mmol, 2.00 equiv), CuI(50.64 mg, 0.27 mmol, 0.10 equiv) and Pd(PPh₃)₄ (307.25 mg, 0.27 mmol,0.10 equiv). The resulting mixture was stirred for overnight at 110° C.under nitrogen atmosphere. The mixture was allowed to cool down to roomtemperature. The reaction was quenched with Water/Ice. The resultingmixture was extracted with EA (3×30 mL). The combined organic layerswere washed with brine (3×100 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withTHF/PE (5%) to afford2-{4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl}-4-fluoropyridine (185.00mg, 27.98%) as white solid. LCMS (ES) [M+1]⁺ m/z: 249.

Step 2

Into a 40 mL vial were added dimethylaminoethanol (1290.35 mg, 14.48mmol, 20.00 equiv) and DMF (20.00 mL). To the above solution was addedNaH (60%) (86.85 mg, 2.172 mmol, 3.00 equiv) in portions at 0° C. Theresulting mixture was stirred for additional 30 min at room temperature.To the above mixture was added2-{4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl}-4-fluoropyridine (180.00mg, 0.72 mmol, 1.00 equiv) in portions at room temperature. Theresulting mixture was stirred for additional 1 h at 50° C. The mixturewas allowed to cool down to room temperature and quenched with sat.NH₄Cl (aq.). The aqueous layer was extracted with DCM:MeOH (10:1) (3×30mL). The combined organic layers were dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withDCM/MeOH (10%) to afford{2-[(2-{4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl}pyridin-4-yl)oxy]ethyl}dimethylamine(145.00 mg, 63.03%) as a yellow solid. LCMS (ES) [M+1]⁺ m/z: 318.

Step 3

Into a 40 mL vial were added{2-[(2-{4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl}pyridin-4-yl)oxy]ethyl}dimethylamine(140.00 mg, 0.44 mmol, 1.00 equiv),N-tert-butyl-2-(methylamino)acetamide hydrochloride (79.59 mg, 0.44mmol, 1.00 equiv), BINAP (54.86 mg, 0.09 mmol, 0.20 equiv), Cs₂CO₃(287.05 mg, 0.88 mmol, 2.00 equiv), 1,4-dioxane (14.00 mL) and Pd(OAc)₂(9.89 mg, 0.04 mmol, 0.10 equiv). The resulting mixture was stirred for1 h at 100° C. under nitrogen atmosphere. The mixture was allowed tocool down to room temperature and quenched with Water/Ice. The aqueouslayer was extracted with DCM:MeOH (10:1) (3×30 mL). The combined organiclayers were dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure. The crude product was purifiedby Prep-HPLC with the following conditions: Column, Sunfire Prep C18 OBDColumn, 50*250 mm 5 um 10 nm; mobile phase, Water (0.1% FA) and ACN (5%Phase B up to 20% in 13 min); Detector, 254. This resulted inN-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[b]pyridin-4-yl)(methyl)amino]acetamide;bis(formic acid) (132.50 mg, 58.11%) as yellow gum. LCMS (ES, m/z):[M+H]⁺: 426. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 8.43 (d, J=5.6 Hz, 1H),8.18 (s, 2HCOOH), 7.86 (d, J=2.5 Hz, 1H), 7.57 (s, 1H), 7.54 (s, 1H),6.97 (dd, J=5.9, 2.6 Hz, 1H), 4.24 (t, J=5.5 Hz, 2H), 3.94 (s, 2H), 3.06(s, 3H), 3.01 (t, J=7.3 Hz, 2H), 2.85 (t, J=7.6 Hz, 2H), 2.79 (t, J=5.8Hz, 2H), 2.32 (s, 6H), 2.02-1.97 (m, 2H), 1.27 (s, 9H).

Example 1.502 Synthesis ofN-tert-butyl-2-{[2-(4-{[(3R)-1-ethylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 496)

Compound 496 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with (3R)-1-ethylpyrrolidin-3-ol. LCMS (ES) [M+1]⁺m/z: 453. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.48 (d, J=5.7 Hz, 1H), 8.28(br, HCOOH), 7.82 (d, J=2.4 Hz, 1H), 7.72 (s, 1H), 7.02 (dd, J=5.7, 2.7Hz, 1H), 5.14-5.08 (m, 1H), 4.12 (s, 2H), 3.27 (s, 3H), 3.14 (t, J=2.4Hz, 2H), 3.06 (dd, J=11.1, 5.7 Hz, 1H), 2.92-2.78 (m, 4H), 2.67-2.60 (m,3H), 2.42-2.30 (m, 1H), 2.04-1.82 (m, 3H), 1.25 (s, 9H), 1.08 (t, J=7.2Hz, 3H).

Example 1.503 Synthesis ofN-tert-butyl-2-{[2-(4-{[(3R)-1-(2-fluoroethyl)pyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 497)

Compound 497 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with (3R)-1-(2-fluoroethyl)pyrrolidin-3-ol. LCMS(ES) [M+1]⁺ m/z: 471. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.47 (d, J=5.6Hz, 1H), 8.17 (1.60 HCOOH), 7.83 (d, J=2.5 Hz, 1H), 7.72 (s, 1H), 7.01(dd, J=5.7, 2.6 Hz, 1H), 5.11-5.01 (m, 1H), 4.61 (t, J=4.9 Hz, 1H), 4.46(t, J=4.9 Hz, 1H), 4.12 (s, 2H), 3.27 (s, 3H), 3.15 (t, J=7.3 Hz, 2H),2.97 (dd, J=10.7, 6.0 Hz, 1H), 2.88-2.73 (m, 5H), 2.71 (t, J=4.9 Hz,1H), 2.60-2.46 (m, 1H), 2.43-2.25 (m, 1H), 2.01-1.96 (m, 2H), 1.89-1.74(m, 1H), 1.25 (s, 9H).

Example 1.504 Synthesis ofN-tert-butyl-2-[methyl({2-[4-(methylsulfanyl)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide(Compound 498)

Compound 498 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with MeSNa. LCMS (ES) [M+1]⁺ m/z: 386. ¹H NMR (300MHz, DMSO-d6, ppm): δ 8.48 (d, J=5.2 Hz, 1H), 8.15 (d, J=1.8 Hz, 1H),7.68 (s, 1H), 7.30 (dd, J=5.3, 2.0 Hz, 1H), 4.14 (s, 2H), 3.27 (s, 3H),3.15 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.58 (s, 3H), 2.08-1.86(m, 2H), 1.25 (s, 9H).

Example 1.505 Synthesis ofN-tert-butyl-2-{[2-(4-{[2-(dimethylamino)ethyl]sulfanyl}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 499)

Compound 499 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with 2-(Dimethylamino)ethanethiol. LCMS (ES) [M+1]⁺m/z: 443. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.47 (d, J=5.2 Hz, 1H), 8.16(s, 0.5HCOOH), 8.15 (d, J=2.5 Hz 1H), 7.67 (s, 1H), 7.33 (dd, J=5.3, 2.0Hz, 1H), 4.14 (s, 2H), 3.26 (s, 3H), 3.25-3.20 (m, 2H), 3.13 (t, J=7.3Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.58 (t, J=7.0 Hz, 2H), 2.23 (s, 6H),2.01-1.96 (m, 2H), 1.25 (s, 9H).

Example 1.506 Synthesis ofN-cyclopropyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide(Compound 500)

Compound 500 was synthesized similar to Compound 348 by replacingtert-butylamine with 1-cyclopropylamine. LCMS (ES) [M+1]⁺ m/z: 411. ¹HNMR (300 MHz, DMSO-d6, ppm): δ 8.48 (d, J=5.6 Hz, 1H), 8.24 (d, J=4.1Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.05 (dd, J=5.7, 2.6 Hz, 1H), 4.26 (t,J=5.5 Hz, 2H), 4.13 (s, 2H), 3.27 (s, 3H), 3.14 (t, J=7.3 Hz, 2H),2.89-2.76 (m, 4H), 2.63 (tq, J=8.3, 4.8 Hz, 1H), 2.36 (s, 6H), 2.04-1.94(m, 2H), 0.67-0.50 (m, 2H), 0.47-0.36 (m, 2H).

Example 1.507 Synthesis ofN-tert-butyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-7-oxo-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 501)

Step 1

Into a 40 mL vial were added 2-methyl-2-(oxan-2-yloxy)propan-1-ol (643mg, 3.69 mmol, 2.00 equiv), DMSO (16 mL) and NaH (60% in mineral oil)(148 mg, 3.70 mmol, 2.00 equiv) at room temperature. The resultingmixture was stirred for 30 min at room temperature. To the above mixturewas addedN-(tert-butyl)-2-((7-((tert-butyldimethylsilyl)oxy)-2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(900 mg, 1.84 mmol, 1.00 equiv) at room temperature. The resultingmixture was stirred for additional 2 h at room temperature. The reactionwas quenched with water (2 mL) and purified by reverse flashchromatography with the following conditions: C18-120 g, column, mobilephase, MeCN in water, 10% to 80% gradient in 10 min, detector, UV 254nm, Flow rate, 70 mL/min. This resulted inN-(tert-butyl)-2-((7-hydroxy-2-(4-(2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(500 mg, 51%) as a yellow solid. LCMS (ES) [M+1]⁺ m/z: 528.

Step 2

Into a 50 mL round-bottom flask were addedN-(tert-butyl)-2-((7-hydroxy-2-(4-(2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(500 mg, 0.95 mmol, 1.00 equiv), DCM (30 mL) and MnO₂ (824 mg, 9.48mmol, 10.00 equiv) at room temperature. The resulting mixture wasstirred for 36 h at room temperature. The resulting mixture wasfiltered, the filter cake was washed with MeOH. The filtrate wasconcentrated under reduced pressure. This resulted inN-(tert-butyl)-2-(methyl(2-(4-(2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide(300 mg, 60%) as a brown solid. LCMS (ES) [M+1]⁺ m/z: 526.

Step 3

Into a 50 mL round-bottom flask were addedN-(tert-butyl)-2-(methyl(2-(4-(2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide(300 mg, 0.57 mmol, 1.00 equiv), dioxane (10 mL) and HCl (gas) (2 M) in1,4-dioxane (0.1 mL) at room temperature. The resulting mixture wasstirred for 1 h at room temperature and concentrated to remove thesolvent. The residue was dissolved in CH₃CN (5 mL) and purified byPrep-HPLC with the following conditions: SunFire Prep C18 OBD Column,19*150 mm, 5 um, mobile phase, water (0.1% TFA) and CH₃CN (36% up to 68%in 7 min). This resulted inN-(tert-butyl)-2-((2-(4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamideas a yellow solid. LCMS (ES) [M−TFA+1]⁺ m/z: 442. ¹H NMR (300 MHz,DMSO-d₆) δ 8.76 (d, J=6.9 Hz, 1H), 8.21 (d, J=2.7 Hz, 1H), 7.90 (s, 1H),7.73 (dd, J=7.0, 2.8 Hz, 1H), 4.37 (s, 2H), 4.22 (s, 2H), 3.60-3.33 (m,5H), 2.77-2.68 (m, 2H), 1.27 (s, 6H), 1.24 (s, 9H).

Example 1.508 Synthesis ofN-tert-butyl-2-{[2-(4-{[(3R,5S)-1,5-dimethylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 502)

Compound 502 was synthesized similar to Compound 348 by replacingdimethylaminoethanol with (3R,5S)-1,5-dimethylpyrrolidin-3-ol. LCMS (ES)[M+1]⁺ m/z: 453. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.45 (d, J=5.6 Hz,1H), 8.17 (s, 1HCOOH), 7.80 (d, J=2.5 Hz, 1H), 7.71 (s, 1H), 6.96 (dd,J=5.6, 2.6 Hz, 1H), 4.99-4.89 (m, 1H), 4.12 (d, J=2.4 Hz, 2H), 3.27 (s,3H), 3.20-3.08 (m, 3H), 2.81 (t, J=7.9 Hz, 2H), 2.60 (dt, J=15.0, 7.8Hz, 1H), 2.53-2.50 (m, 1H), 2.22 (s, 3H), 2.27-2.13 (m, 1H), 2.06-1.94(m, 2H), 1.54-1.39 (m, 1H), 1.25 (s, 9H), 1.09 (d, J=6.0 Hz, 3H).

Example 1.509 Synthesis of(2R)—N-tert-butyl-2-{methyl[2-(4-{[(3R)-1-methylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide(Compound 503)

Compound 503 was synthesized similar to Compound 101 by replacing4-methoxy-2-(tributylstannyl)pyridine with(R)-4-((1-methylpyrrolidin-3-yl)oxy)-2-(trimethylstannyl)pyridine. LCMS(ES) [M+1]⁺ m/z: 453. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.48 (d, J=5.7Hz, 1H), 8.19 (s, 2H), 7.85 (d, J=2.5 Hz, 1H), 7.79 (s, 1H), 7.01 (dd,J=5.6, 2.6 Hz, 1H), 5.10 (t, J=4.6 Hz, 1H), 5.04 (q, J=7.2 Hz, 1H),3.29-2.99 (m, 2H), 3.13 (s, 3H), 2.95 (dd, J=10.9, 5.8 Hz, 1H),2.87-2.71 (m, 4H), 2.58-2.50 (m, 1H), 2.44-2.37 (m, 1H), 2.36 (s, 3H),2.14-1.76 (m, 3H), 1.33 (d, J=7.0 Hz, 3H), 1.21 (s, 9H).

Example 1.510 Synthesis of(2R)-2-{methyl[2-(4-{[(3R)-1-methylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(propan-2-yl)propanamide(Compound 504)

Compound 504 was synthesized similar to Compound 101 by replacing4-methoxy-2-(tributylstannyl)pyridine with(R)-4-((1-methylpyrrolidin-3-yl)oxy)-2-(trimethylstannyl)pyridine and byreplacing tert-butylamine with isopropylamine. LCMS (ES) [M+1]⁺ m/z:439. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.49 (d, J=5.6 Hz, 1H), 8.18 (s,HCOOH), 8.17 (d, J=9.1 Hz, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.01 (dd, J=5.6,2.6 Hz, 1H), 5.17-5.08 (m, 1H), 5.06 (q, J=6.9 Hz, 1H), 3.98-3.80 (m,1H), 3.31-3.02 (m, 2H), 3.11 (s, 3H), 2.99-2.71 (m, 5H), 2.56-2.51 (m,1H), 2.46-2.36 (m, 1H), 2.36 (s, 3H), 2.10-1.78 (m, 3H), 1.34 (d, J=7.0Hz, 3H), 1.08 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H).

Example 1.511 Synthesis of2-[methyl(2-{4-[2-(thiomorpholin-4-yl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]-N-(propan-2-yl)acetamide(Compound 505)

Compound 505 was synthesized similar to Compound 389 by replacingdimethylaminoethanol with 2-thiomorpholinoacetate and by replacingtert-butylamine with isopropyl amine. LCMS (ES) [M+1]⁺ m/z: 471. ¹H NMR(300 MHz, DMSO-d6, ppm): δ 8.47 (d, J=5.6 Hz, 1H), 7.99 (d, J=7.8 Hz,1H), 7.80 (d, J=2.6 Hz, 1H), 7.05 (dd, J=5.6, 2.6 Hz, 1H), 4.22 (t,J=5.7 Hz, 2H), 4.15 (s, 2H), 3.87 (dq, J=13.4, 6.7 Hz, 1H), 3.27 (s,3H), 3.15 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.78 (dd, J=6.1,4.0 Hz, 6H), 2.64-2.57 (m, 4H), 2.05-1.93 (m, 2H), 1.04 (d, J=6.6 Hz,6H).

Example 1.512 Synthesis ofN-tert-butyl-2-[methyl(2-{4-[2-(methylsulfanyl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(Compound 506)

Into a 50 mL round-bottom flask were added2-{[2-(4-{[(tert-butylcarbamoyl)methyl](methyl)amino}-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl)pyridin-4-yl]oxy}ethylmethanesulfonate (500 mg, 1.05 mmol, 1.00 equiv), DMF (5.0 mL) and(methylsulfanyl)sodium (220 mg, 3.14 mmol, 3.00 equiv) at roomtemperature. The resulting mixture was stirred for 2 h at 60° C. Thereaction was cooled to room temperature and quenched with water (1.0mL), purified by reverse flash chromatography with the followingconditions: C18 silica gel, mobile phase, water (0.05% NH₃·H₂O), 10% to80% gradient in 10 min, detector, UV 254 nm. This resulted inN-tert-butyl-2-[methyl(2-{4-[2-(methylsulfanyl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(400 mg, 89%) as a yellow semi-solid. LCMS (ES) [M+1]⁺ m/z: 430. ¹H NMR(400 MHz, DMSO-d6, ppm): δ 8.48 (d, J=5.6 Hz, 1H), 7.84 (d, J=2.4 Hz,1H), 7.67 (s, 1H), 7.05 (dd, J=5.6, 2.8 Hz, 1H), 4.30 (t, J=6.4 Hz, 2H),4.12 (s, 2H), 3.32 (s, 3H), 3.14 (t, J=6.8 Hz, 2H), 2.88 (t, J=6.8 Hz,2H), 2.50 (t, J=1.6 Hz, 2H), 2.17 (s, 3H), 2.0 (m, 2H), 1.24 (s, 9H).

Example 1.513 Synthesis ofN-tert-butyl-2-({2-[4-(2-methanesulfonylethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(Compound 507)

Into a 40 mL vial were addedN-tert-butyl-2-[methyl(2-{4-[2-(methylsulfanyl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide(200 mg, 0.47 mmol, 1.00 equiv), THE (4.0 mL), H₂O (0.5 mL) andpotassium peroxymonosulfate (1.14 g, 1.86 mmol, 4.00 equiv) at 0° C. Theresulting mixture was stirred for 2 h at room temperature. The residuewas dissolved in MeOH (10 mL). The resulting mixture was filtered, thefilter cake was washed with MeOH (2*5 mL). The filtrate was concentratedunder reduced pressure. The residue was dissolved in MeOH (5 mL) andpurified by Prep-HPLC with the following conditions: Sunfire Prep C18OBD Column, 50*250 mm, 5 μm, 10 nm, mobile phase, water (0.1% FA) andCH₃CN (5% up to 35% in 12 min) to affordN-tert-butyl-2-({2-[4-(2-methanesulfonylethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamideformate (124.8 mg, 53%) as a white solid. LCMS (ES) [M+1]⁺ m/z 462. ¹HNMR (400 MHz, DMSO-d₆) δ 8.52 (d, J=5.6 Hz, 1H), 8.15 (s, 1H), 7.85 (d,J=2.5 Hz, 1H), 7.64 (s, 1H), 7.12 (dd, J=5.6, 2.6 Hz, 1H), 4.53 (t,J=5.7 Hz, 2H), 4.15 (s, 2H), 3.68 (t, J=5.7 Hz, 2H), 3.25 (s, 3H), 3.14(t, J=7.28 Hz, 2H), 3.11 (s, 3H), 2.82 (t, J=7.8 Hz, 2H), 2.00-1.96 (m,2H), 1.24 (s, 9H).

Example 1.513 Synthesis ofN-tert-butyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}((2H3)methyl)amino)acetamide(Compound 509)

Step 1

A mixture ofN-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}amino)acetamide(2 g, 7.073 mmol, 1.00 equiv), (Boc)₂O (3.09 g, 14.146 mmol, 2 equiv),TEA (1.43 g, 14.146 mmol, 2 equiv) and DMAP (0.17 g, 1.415 mmol, 0.2equiv) in DCM (30 mL) was stirred for 24 h at room temperature. Theresulting mixture was extracted with CH₂Cl₂ (3×100 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with PE/THE (2:1)to afford tert-butyl(2-(tert-butylamino)-2-oxoethyl)(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)carbamate(1.6 g, 59.08%) as a white solid. LCMS (ES) [M+1]⁺ m/z: 383.

Step 2

A mixture of tert-butyl(2-(tert-butylamino)-2-oxoethyl)(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)carbamate(1 g, 2.612 mmol, 1.00 equiv), 4-fluoro-2-(tributylstannyl)pyridine(1.51 g, 3.918 mmol, 1.5 equiv) and Pd(PPh₃)₄ (0.60 g, 0.522 mmol, 0.2equiv) in Toluene (20 mL) was stirred for 16 h at 100 degrees C. undernitrogen atmosphere. The resulting mixture was concentrated undervacuum. The residue was purified by silica gel column chromatography,eluted with PE/THE (1:1) to afford tert-butylN-[(tert-butylcarbamoyl)methyl]-N-[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]carbamate1.0 g (86.33%) as an off-white solid. LCMS (ES) [M+1]⁺ m/z: 444.

Step 3

To a stirred solution of tert-butylN-[(tert-butylcarbamoyl)methyl]-N-[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]carbamate(500 mg, 1.127 mmol, 1.00 equiv) in EA (20 mL, 204.301 mmol, 181.22equiv) was added HCl in ether (2M) (1.69 mL, 3.381 mmol, 3 equiv) inportions at room temperature. The resulting mixture was concentratedunder reduced pressure to affordN-tert-butyl-2-{[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamidehydrochloride (360 mg, 92.99%) as a white solid. LCMS (ES) [M−HCl+1]+m/z: 344.

Step 4

To a stirred solution ofN-tert-butyl-2-{[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide(360 mg, 1.048 mmol, 1.00 equiv) in DMF was added NaH (50.31 mg, 2.096mmol, 2 equiv) in portions at 0 degrees C. under nitrogen atmosphere.The resulting mixture was stirred for 20 min at 0 degrees C. undernitrogen atmosphere. To the above mixture was added CD₃I (227.94 mg,1.572 mmol, 1.50 equiv) dropwise at 0 degrees C. The resulting mixturewas stirred for additional 6 h at room temperature. The resultingmixture was extracted with CH₂Cl₂ (3×50 mL). The combined organic layerswere dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with PE/EA (1:4) to affordN-(tert-butyl)-2-((2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl-d3)amino)acetamide(300 mg, 79.39%) as a white solid. LCMS (ES) [M+1]⁺ m/z: 361.

Step 5

To a stirred solution of 2-methyl-2-(oxan-2-yloxy)propan-1-ol (435.05mg, 2.496 mmol, 3 equiv) in DMF (30 mL) was added NaH (39.95 mg, 1.664mmol, 2 equiv) in portions at 0 degrees C. under nitrogen atmosphere.The resulting mixture was stirred for 20 min at 0 degrees C. undernitrogen atmosphere. To the above mixture was addedN-(tert-butyl)-2-((2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl-d3)amino)acetamide(300 mg, 0.832 mmol, 1.00 equiv) in portions at 0 degrees C. Theresulting mixture was stirred for additional 4 h at room temperature.The resulting mixture was extracted with CH₂Cl₂ (3×30 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with PE/EA (1:4) toaffordN-(tert-butyl)-2-((methyl-d3)(2-(4-(2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide(300 mg, 70.03%) as a white solid. LCMS (ES) [M+1]⁺ m/z: 515.

Step 6

A mixture ofN-(tert-butyl)-2-((methyl-d3)(2-(4-(2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide(300 mg, 0.583 mmol, 1.00 equiv) in EtOAc (5 mL) and HCl (g) in ether(2M) (0.58 mL, 1.166 mmol, 2 equiv) was stirred for 3 h at roomtemperature. The crude product was purified by Prep-HPLC with thefollowing conditions (Prep-HPLC-001): Column, Sunfire Prep C18 OBDColumn, 50*250 mm, 5 μm 10 nm; mobile phase, Water (0.1% FA) and ACN (5%PhaseB up to 25% in 15 min) to affordN-(tert-butyl)-2-((2-(4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl-d3)amino)acetamide(175.9 mg, 70.09%) as a yellow green solid. LCMS (ES) [M+1]⁺ m/z: 431.¹H NMR (300 MHz, DMSO-d₆) δ 8.47 (d, J=5.6 Hz, 1H), 7.83 (d, J=2.5 Hz,1H), 7.68 (s, 1H), 7.05 (dd, J=5.9, 2.6 Hz, 1H), 4.13 (s, 2H), 3.86 (s,2H), 3.14 (t, J=7.2 Hz, 2H), 2.81 (t, J=7.7 Hz, 2H), 2.04-1.93 (m, 2H),1.25 (s, 9H), 1.24 (s, 6H).

Example 1.513 Synthesis ofN-tert-butyl-2-{[2-(4-{2-[di(2H3)methylamino]ethoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(Compound 508)

Step 1

To a stirred solution ofN-tert-butyl-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide(1.4 g, 3.50 mmol, 1.00 equiv) in DCM (20 mL) at 0° C. were added TEA(709 mg, 7.00 mmol, 2.0 equiv) and methanesulfonyl chloride (482 mg,4.20 mmol, 1.2 equiv) dropwise. The resulting mixture was stirred for 2h at room temperature and was diluted with 30 mL H₂O. The mixture wasextracted with CH₂Cl₂ (3×20 mL). The combined organic layers were washedwith brine (50 mL), dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH(10:1) to afford2-{[2-(4-{[(tert-butylcarbamoyl)methyl](methyl)amino}-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl)pyridin-4-yl]oxy}ethylmethanesulfonate (1.3 g, 77.6%) as a white solid. LCMS (ES) [M+1]⁺ m/z:478.

Step 2

To a stirred mixture of2-{[2-(4-{[(tert-butylcarbamoyl)methyl](methyl)amino}-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl)pyridin-4-yl]oxy}ethylmethanesulfonate (300 mg, 0.62 mmol, 1.00 equiv) and bis(methyl-d3)aminehydrochloride (64 mg, 1.25 mmol, 2.00 equiv) in CH₃CN (5 mL) was addedCs₂CO₃ (818 mg, 2.51 mmol, 4.00 equiv). The resulting mixture wasstirred for 3 h at 60° C. The mixture was cooled down to roomtemperature and filtered. The filtrate was purified by Prep-HPLC withthe following conditions: XBridge Prep C18 OBD Column, 19*150 mm, 5 um,mobile phase, water (10 mmol/L NH₄HCO₃) and CH₃CN (30% Phase B up to 40%in 7 min), Detector, UV 254 nm. The desired fraction was freeze-dried toaffordN-tert-butyl-2-{[2-(4-{2-[di(2H3)methylamino]ethoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide(114.7 mg, 42.2%) as a white solid. LCMS (ES) [M+1]⁺ m/z: 433. ¹H NMR(300 MHz, DMSO-d₆) δ 8.47 (d, J=5.6 Hz, 1H), 7.84 (d, J=2.6 Hz, 1H),7.68 (s, 1H), 7.05 (dd, J=5.7, 2.6 Hz, 1H), 4.19 (t, J=5.7 Hz, 2H), 4.13(s, 2H), 3.27 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H),2.66 (t, J=5.7 Hz, 2H), 2.01-1.96 (m, 2H), 1.25 (s, 9H).

2. BIOLOGICAL EXAMPLES Example 2.1 Biological In-Vitro FerroportinInternalization Assay

The protocol for this assay is generally as described in WO2018/128828,incorporated herein by reference in its entirety. Functionalinternalization of ferroportin protein was measured using astably-transfected CHO cell line expressing the human ferroportin taggedto a luciferase reporter. Cells were plated for 24 h in the presence offerric ammonium citrate (FAC). Ferroportin protein expression wasinduced with doxycycline for 24 h. The next day, the compounds wereadded. Test compounds were dissolved in DMSO. Cells were incubated withthe test compounds for 6 h, and subsequently luciferase activity wasmeasured using the Nano-Glo Luciferase Assay System and Glomax (Promega,Madison, Wis.).

The average pEC₅₀ was determined for the test compounds. The data isprovided in Table 2 below.

TABLE 2 Cmpd No. from Table 1 pEC₅₀ 1 6.9 2 6.6 3 6.8 4 6.4 5 6.2 6 6.57 6.6 8 5 9 6.2 10 6.6 11 6.3 12 5.8 13 6.4 14 6.8 15 6.9 16 6.6 17 6.618 7.1 19 5.4 20 6.7 21 6.9 22 7 23 6.9 24 7.6 25 7.1 26 6.6 27 6.8 285.9 29 5.9 30 5.7 31 6.2 32 7.2 33 5.7 34 7.9 35 7 36 7.3 37 6.6 38 6.639 6.3 40 7.1 41 7.3 42 7.3 43 7 44 7.9 45 7.2 46 5.1 47 5.7 48 6.8 497.1 50 5.6 51 7.5 52 6.8 53 6.6 54 6.9 55 6.3 56 6.7 57 7.5 58 6.7 596.8 60 7.6 61 7.1 62 7.6 63 7.2 64 7.8 65 7.6 66 7.7 67 6.6 68 7.2 69 770 7.4 71 5.9 72 5.5 73 6.8 74 7.5 75 7.5 76 6 77 7 78 7.4 79 6.5 80 6.881 6.8 82 6.8 83 6.9 84 6.6 85 5.5 86 6.8 87 6.6 88 7.1 89 7.3 90 7.4 917.3 92 6.5 93 6.1 94 6.3 95 7.3 96 6.6 97 7.1 98 7 99 7.3 100 7.5 1018.2 102 7.1 103 6.4 104 7.2 105 7.7 106 5.4 107 5.7 108 7.6 109 7 1107.9 111 7.2 112 8 113 7.7 114 7.6 115 7.1 116 7.4 117 6.9 118 7.8 1197.7 120 7.2 121 7.9 122 7.8 123 7.2 124 7 125 7.5 126 7.9 127 7.1 1287.4 129 7.2 130 6.9 131 7.1 132 7.3 133 7 134 6.9 135 7.4 136 7.7 1377.8 138 7.8 139 7.5 140 7 141 7.1 142 7.4 143 7.2 144 7.5 145 6.9 1466.8 147 6.7 148 7.6 149 7.2 150 7.3 151 8.1 152 7.9 153 7.6 154 7.4 1557.5 156 7.9 157 7.3 158 6.2 159 8.0 160 5.2 161 7.4 162 5.7 163 5.4 1645.0 165 7.4 166 6.7 167 7.9 168 7.3 169 7.3 170 7.8 171 7.2 172 7.5 1736.8 174 8.2 175 <5.0 176 7.8 177 6.9 178 7.2 179 7.7 180 5.2 181 6.5 1827.6 183 8 184 7.7 185 7.2 186 7 187 7.9 188 6.7 189 7.7 190 7.8 191 7192 6.5 193 6.8 194 5.4 195 6.9 196 5.6 197 7.4 198 8.1 199 7.9 200 7.6201 7.4 202 7.5 203 6.3 204 6.9 205 7.5 206 6.9 207 7.2 208 5.7 209 8210 7.9 211 7.9 212 7.1 213 6.4 214 7.8 215 7.5 216 6.6 217 6.9 218 7219 7.1 220 7 221 7 222 7.2 223 7.8 224 7.9 225 6.8 226 7.1 227 7.2 2287.1 229 7.9 230 6.6 231 6.2 232 7 233 7.4 234 6.4 235 7.5 236 7.4 2377.1 238 7.5 239 7.8 240 7.1 241 8 242 7.7 243 7.4 244 6.4 245 7.7 2467.3 247 7.2 248 7.1 249 7.2 250 7.4 251 8.3 252 7.9 253 7.6 254 7 2556.9 256 6.6 257 7 258 6.3 259 7.1 260 7.6 261 7.6 262 7.1 263 8 264 6.5265 7.5 266 7.3 267 7.1 268 6 269 8.4 270 7.5 271 7.4 272 7.8 273 7.8274 6.8 275 7 276 7.7 277 8.2 278 7.8 279 8.2 280 8.3 281 7.3 282 7.5283 6.6 284 7.7 285 7.8 286 7.5 287 7.2 288 7.1 289 7.5 290 7.6 291 7.3292 8.1 293 7.9 294 7.9 295 7 296 7.6 297 7.5 298 6.1 299 6.1 300 6.2301 6.9 302 7.9 303 6.4 304 6.8 305 7.8 306 6.6 307 7.4 308 8.1 309 8.1310 7.4 311 8.4 312 7.7 313 7.3 314 7.6 315 6.8 316 7.8 317 7.9 318 7.9319 6.4 320 7.1 321 7.1 322 7.7 323 7.5 324 7.4 325 7.9 326 7.9 327 7.9328 6.8 329 6.8 330 7.8 331 8.3 332 7.8 333 7.8 334 7.2 335 8.4 336 7.8337 7.4 338 7.1 339 8.2 340 7.7 341 7.6 342 7.6 343 7.7 344 7.6 345 6.7346 7.6 347 7.6 348 8.0 349 7.8 350 7.7 351 7.6 352 7.6 353 7.8 354 7.7355 7.7 356 8.3 357 7.7 358 7.7 359 7.5 360 7.8 361 8.1 362 8 363 8.3364 8.1 365 7.4 366 7.7 367 8 368 7.8 369 7.7 370 8.2 371 7.5 372 7.5373 7.3 374 7.2 375 8 376 8 377 7.8 378 8 379 7.2 380 6.6 381 8.3 3827.8 383 7.8 384 8.1 385 8.2 386 8.4 387 8.2 388 8.2 389 7.9 390 7.8 3917.7 392 8.3 393 8.1 394 8.3 395 8.4 396 8.5 397 7.6 398 8.1 399 7.5 4008.2 401 8.3 402 7.8 403 7.6 404 8 405 8.3 406 7.7 407 6.6 408 8.5 4097.6 410 7.3 411 8.2 412 8.1 413 8 414 8.3 415 7.7 416 8 417 7.1 418 7.5419 7.6 420 8 421 8.2 422 7.4 423 7.7 424 7 425 8.3 426 8.4 427 7.6 4287.5 429 8 430 8 431 7.4 432 7.5 433 8.0 434 7.4 435 7.8 436 7.3 437 8.0438 7.7 439 7.8 440 8 441 7.5 442 8 443 7.8 444 7.9 445 8.3 446 8.2 4477.6 448 7.4 449 7.2 450 6.4 451 7.8 452 8.4 453 8.1 454 7.9 455 7.7 4566.2 457 6.3 458 7.3 459 7.3 460 8.2 461 8.3 462 8.4 463 8.1 464 8.0 4658.3 466 7.9 467 8.3 468 8.5 469 8.3 470 7.2 471 7.4 472 7.4 473 8.3 4748.3 475 7.6 476 6.7 477 6.9 478 7.6 479 7.9 480 7.3 481 7.7 482 6.1 4837.2 484 7 485 7.1 486 7.4 487 7.5 488 7.8 489 8.2 490 7.9 491 8.2 4926.6 493 6.9 494 6.3 495 7.4 496 8.0 497 8.2 498 7.5 499 8.2 500 7.3 5016.4 502 8.2 503 8.5 504 7.9 505 8.8 506 8.0 507 7.9 508 7.6 509 8.2

Efforts have been made to ensure accuracy with respect to numbers used(e.g., amounts, temperature, etc.) but some experimental errors anddeviations should be accounted for.

One skilled in the art will recognize many methods and materials similaror equivalent to those described herein, which could be used in thepracticing the subject matter described herein. The present disclosureis in no way limited to just the methods and materials described.

Unless defined otherwise, technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this subject matter belongs, and are consistent with:Singleton et al (1994) Dictionary of Microbiology and Molecular Biology,2nd Ed., J. Wiley & Sons, New York, N.Y.; and Janeway, C., Travers, P.,Walport, M., Shlomchik (2001) Immunobiology, 5th Ed., GarlandPublishing, New York.

Throughout this specification and the claims, the words “comprise,”“comprises,” and “comprising” are used in a non-exclusive sense, exceptwhere the context requires otherwise. It is understood that embodimentsdescribed herein include “consisting of” and/or “consisting essentiallyof” embodiments.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit, unlessthe context clearly dictates otherwise, between the upper and lowerlimit of the range and any other stated or intervening value in thatstated range, is encompassed. The upper and lower limits of these smallranges which may independently be included in the smaller rangers isalso encompassed, subject to any specifically excluded limit in thestated range. Where the stated range includes one or both of the limits,ranges excluding either or both of those included limits are alsoincluded.

Many modifications and other embodiments set forth herein will come tomind to one skilled in the art to which this subject matter pertainshaving the benefit of the teachings presented in the foregoingdescriptions and the associated drawings. Therefore, it is to beunderstood that the subject matter is not to be limited to the specificembodiments disclosed and that modifications and other embodiments areintended to be included within the scope of the appended claims.Although specific terms are employed herein, they are used in a genericand descriptive sense only and not for purposes of limitation.

That which is claimed:
 1. A compound of Formula (I′):

or a pharmaceutically acceptable salt thereof; wherein, Z is N; Ring Bis

 wherein indicates the point of attachment to the remainder of themolecule; R⁶, in each instance, is selected from the group consisting ofhalogen, hydroxy, C₁-C₃ alkoxy, C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₃ alkyl,hydroxy-C₁-C₁₀ alkoxy, hydroxy-C₁-C₁₀-alkyl, cyano, —NR^(G)R^(H),halo-C₁-C₃ alkoxy, —O—(C₁-C₆ alkyl)-R^(bb), —O—R^(bb), —(C₁-C₆alkyl)-NR^(GI)R^(HI), —S—C₁-C₃ alkyl, —S—C₁-C₃ alkyl-NR^(G1)R^(H1),halo-C₁-C₃ alkyl, —O—R^(cc)—O—R^(dd), 5- to 7-membered monocyclicheteroaryl, and C₃-C₆ cycloalkyl; wherein, the alkyl moiety inhydroxy-C₁-C₁₀ alkoxy or —O—(C₁-C₆ alkyl)-R^(bb) is optionallysubstituted with cyano, hydroxy, hydroxy-C₁-C₃-alkyl, halogen, or C₁-C₃alkoxy; R^(bb) is 4- to 7-membered monocyclic or bridged heterocyclyl,C₃-C₇ cycloalkyl, 5- or 6-membered monocyclic heteroaryl, —SO₂—C₁-C₃alkyl, —S—C₁-C₃ alkyl, —C(O)NR^(G1)R^(H1), or —NR^(G)R^(H); R^(cc) isC₁-C₃ alkyl; and R^(dd) is C₁-C₃ alkyl or a 6-membered heteroaryl; wherein, said cycloalkyl, heterocyclyl, or heteroaryl of R⁶, R^(bb), orR^(dd) is optionally substituted with one or two substituents, eachindependently selected from the group consisting of hydroxy, halogen,halo-C₁-C₃ alkyl, oxo, C₁-C₃ alkoxy, and C₁-C₃ alkyl; R^(G1) and R^(H1)are each independently hydrogen or C₁-C₃ alkyl; and, R^(G) and R^(H) areeach independently hydrogen, —C(O)R^(Ga), or optionally deuterated C₁-C₃alkyl; wherein, R^(Ga) is C₁-C₃ alkyl or hydrogen; or, two R⁶ groups,taken together with the atom to which each is attached, form a 5- or6-membered monocyclic heterocyclyl fused with Ring B, a C₄-C₇ cycloalkylfused with Ring B, a phenyl fused with Ring B, or a 5- to 6-memberedmonocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl,phenyl, cycloalkyl, or heteroaryl fused with ring B is optionallysubstituted with one or two substituents, each independently selectedfrom the group consisting of C₁-C₃ alkoxy, hydroxy, hydroxy-C₁-C₃-alkyl,C₁-C₃ alkyl, C₃-C₇ cycloalkyl, and 5- or 6-membered monocyclicheterocyclyl; n is 0, 1, 2, or 3; Y¹, Y², Y³, and Y⁴ are eachindependently selected from the group consisting of CH, N, NH, O, S, SH,S—R⁶, N—R⁶, and C—R⁶, provided that 1 or 2 of Y¹, Y², Y³, and Y⁴ can beN, N—R⁶, NH, O, SH or S—R⁶; f is 0 or 1; p is 1 or 2; R^(X), in eachinstance, is halogen, C₁-C₆ alkyl, C₁-C₃ alkoxy, hydroxy, oxo, or cyano;m is 0, 1, or 2; R³ is selected from the group consisting of hydrogen,optionally deuterated C₁-C₃ alkyl, hydroxy-C₁-C₃ alkyl, halo-C₁-C₃alkyl, cyclopropyl, and phenyl; R⁴ is

wherein, R^(4a) and R^(4b) are each independently selected from thegroup consisting of hydrogen, C₁-C₁₀ alkyl, hydroxy-C₁-C₆ alkyl,halo-C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₆ alkyl, —C₁-C₆ alkyl-NR^(J1)R^(J2),C₃-C₇ cycloalkyl, 4- to 10-membered monocyclic, fused bicyclic, bridgedbicyclic, or spiro heterocyclyl, C₆-C₁₀ monocyclic or fused bicyclicaryl, 5- to 10-membered monocyclic or fused bicyclic heteroaryl, (C₆-C₁₀monocyclic or fused bicyclic aryl)-C₁-C₃ alkyl, and (5- to 10-memberedmonocyclic or fused bicyclic heteroaryl)-C₁-C₃ alkyl;  R^(J1) and R^(J2)are independently hydrogen or C₁-C₃ alkyl;  wherein the cycloalkyl,heterocyclyl, aryl, heteroaryl, aryl-alkyl, or heteroaryl-alkyl ofR^(4a) or R^(4g) is optionally substituted with one, two, or threesubstituents, each independently selected from the group consisting ofhalogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl, hydroxy, C₁-C₃ alkoxy,halo-C₁-C₃ alkoxy, oxo, C₃-C₇ cycloalkyl, and 5- to 10-memberedmonocyclic, fused bicyclic, or spiro heterocyclyl;  R^(4b) is hydrogenor C₁-C₆ alkyl; or  R^(4a) and R^(4b) taken together with the atom towhich each is attached form a 5- to 10-membered monocyclic, fusedbicyclic, or bridged bicyclic heterocyclyl, optionally substituted withone or two substituents, each independently selected from the groupconsisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl, hydroxy, and C₁-C₃alkoxy; or  R^(4b) and R^(4c) taken together with the atom to which eachis attached form a 5- to 7-membered monocyclic heterocyclyl optionallysubstituted with one, two, or three substituents, each independentlyselected from the group consisting of hydroxy, halogen, and C₁-C₃ alkyl;or  R^(4c) and R^(4d) are each independently selected from the groupconsisting of hydrogen, C₁-C₃ alkoxy, hydroxy, C₁-C₃ alkyl-thio-C₁-C₃alkyl, hydroxy-C₁-C₆ alkyl, C₁-C₆ alkoxy-C₁-C₃ alkyl, C₃-C₇ cycloalkyl,and C₁-C₃ alkyl; or R^(4c) and R^(4d) taken together with the atom towhich each is attached form a C₃-C₇ cycloalkyl.
 2. The compound of claim1, or a pharmaceutically acceptable salt thereof wherein p is
 1. 3. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Y¹, Y², Y³, and Y⁴ are each CH or C—R⁶.
 4. The compound of claim3, a pharmaceutically acceptable salt thereof, wherein Y¹ is CH, Y² isC—R⁶, Y³ is CH, and Y⁴ is CH.
 5. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Y³ is N and Y¹, Y²,and Y⁴ are each CH or C—R⁶.
 6. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Y² is N and Y¹, Y³, Y⁴are each CH or C—R⁶.
 7. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁶, in each instance, is selected fromthe group consisting of halogen, hydroxy, C₁-C₃ alkoxy, C₁-C₃ alkyl,C₁-C₃ alkoxy-C₁-C₃ alkyl, hydroxy-C₁-C₁₀ alkoxy, hydroxy-C₁-C₁₀-alkyl,—O—(C₁-C₆ alkyl)-R^(bb), halo-C₁-C₃ alkoxy, —O—R^(cc)—O—R^(dd),halo-C₁-C₃ alkyl, —(C₁-C₆ alkyl)- NR^(GI)R^(HI), —S—CH₃,—S(CH₂)₂N(CH₃)₂, and —NR^(G)R^(H); wherein, R^(bb) is —NR^(G)R^(H),—C(O)N(CH₃)₂, —S(O)₂CH₃, or —SCH₃; R^(G) and R^(H) are eachindependently hydrogen, optionally deuterated C₁-C₃ alkyl, or—C(O)R^(G)a, wherein R^(Ga) is C₁-C₃ alkyl; R^(GI) and R^(HI) are eachindependently hydrogen or C₁-C₃ alkyl; R^(cc) and R^(dd) are eachindependently C₁-C₃ alkyl; and, wherein the alkyl moiety inhydroxy-C₁-C₁₀ alkoxy is optionally substituted with hydroxy, halogen,or C₁-C₃ alkoxy.
 8. The compound of claim 7, or a pharmaceuticallyacceptable salt thereof, wherein R⁶, in each instance, is selected fromthe group consisting of methoxy, ethoxy, methyl, fluoro, chloro, ethyl,—N(CH₃)₂, hydroxy, —OCH₂CH₂OH, —CH₂OH, —CH₂OCH₃, —OCH₂CH₂NH₂,OCH₂CH₂N(CH₃)₂, —OCH₂C(CH₃)₂OH, —OCH₂CF₃, —OCHF₂, —OCF₃, —OCH₂CH₂OCH₃,—OCH₂C H₂F, —OC(CH₃)₂CH₂OH, —OCH₂CH(CH₃)OH, —OCH₂CH₂NHC(O)CH₃,—OC(CH₃)₂CH₂N(CH₃)₂, —OCH(CH₃)CH₂OH, —OCH₂CH(CH(CH₃)₂)OH,—OCH₂CH(CH₂CH₃)OH, —OCH₂C(CH₂CH₃)₂OH, —OCH₂CH₂N(CH₂CH₃)₂,—OCH(CH₃)CH₂N(CH₃)₂, —OCH₂C(O)N(CH₃)₂, —OCH₂C(CH₃)₂N(CH₃)₂,—OCH₂CH(CH₂OH)OH, —OCH₂CH₂NH(CH₃), —OCH₂CH(CF₃)OH, —OCH₂C(CH₃)(CH₂CH₃)OH, —OCH₂CH(CH₂OCH₃)OH, —OCH₂CH(CH₂F)OH, —(CH₂)₃N(CH₃)₂, —(CH₂)₃N(CH₃)H,—O(CH₂)₂S(O)₂CH₃, —O(CH₂)₂SCH₃, —(CH₂)₂C(CH₃)₂OH, —OCH₂CH₂N(CD₃)₂, and—CH₂CH₂OH.
 9. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁶, in each instance, is selected from the groupconsisting of —O—(C₁-C₆ alkyl)-R^(bb), —O—R^(cc)—O—R^(dd), 5- to7-membered monocyclic heteroaryl, and C₃-C₆ cycloalkyl; wherein, R^(cc)is C₁-C₃ alkyl and R^(dd) is 6-membered heteroaryl; R^(bb) is 4- to7-membered monocyclic or bridged heterocyclyl, 5- or 6-memberedmonocyclic heteroaryl, or C₃-C₇ cycloalkyl; and wherein said cycloalkyl,heteroaryl, or heterocyclyl of R⁶, R^(bb), or R^(dd) is optionallysubstituted with one or two substituents, each independently selectedfrom the group consisting of hydroxy, halogen, C₁-C₃ alkoxy, oxo,halo-C₁-C₃ alkyl, and C₁-C₃ alkyl.
 10. The compound of claim 9, or apharmaceutically acceptable salt thereof, wherein R⁶, in each instance,is selected from the group consisting of cyclopropyl, —O—R^(bb),—O—(CH₂)—R^(bb), —O—(CH₂)₂—R^(bb), —O—(CH₂)₂—O-pyridazinyl, andoptionally C₁-C₃ alkyl-substituted imidazolyl; wherein, R^(bb) isselected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranol, oxetanyl,dioxolanyl, azetidinyl, morpholinyl, piperazinyl,2-oxa-5-azabicyclo[2.2.1]heptane, imidazolyl, tetrazolyl, pyridazinyl,piperidinyl, thiomorpholinyl, and pyrrolidinyl, each optionallysubstituted with hydroxy, oxo, fluoro, —CF₃, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂F, methoxy, ethyl, or methyl.
 11. The compound of claim 10, apharmaceutically acceptable salt thereof wherein R⁶, in each instance,is selected from the group consisting of

where

indicates the point of attachment to Ring B.
 12. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein two R⁶ groups,taken together with the atom to which each is attached, form a 5- or6-membered monocyclic heterocyclyl fused with Ring B, a C₄-C₇ cycloalkylfused with Ring B, a phenyl fused with Ring B, or a 5- or 6-memberedmonocyclic heteroaryl fused with Ring B, each optionally substitutedwith one or two substituents, each independently selected from the groupconsisting of C₁-C₃ alkoxy, hydroxy, hydroxy-C₁-C₃-alkyl, C₁-C₃ alkyl,C₃-C₇ cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl.
 13. Thecompound of claim 12, or a pharmaceutically acceptable salt thereof,wherein two R⁶ groups, taken together with the atom to which each isattached, form a pyrazolyl, dioxanyl, pyridinyl, pyrimidinyl, thiazolyl,furanyl, dioxolanyl, or phenyl ring fused with Ring B, wherein said ringis optionally substituted with one substituent selected from the groupconsisting of hydroxy, methoxy, tetrahydropyranyl, —CH₂OH, and methyl.14. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein f is
 1. 15. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein f is 0 and Ring B is

wherein, n is 0 or 1; and Y² and Y³ are each independently selected fromthe group consisting of CH, N, NH, NR⁶, S, O, and CR⁶, provided thatonly one of Y² and Y³ can be N, NH, NR⁶, S, or O.
 16. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1.17. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R³ is selected from the group consisting of hydrogen,methyl, —CD₃, ethyl, phenyl, —CH₂CF₃, and —CH₂CH₂OH.
 18. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R³ ismethyl.
 19. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁴ is a (5- to 10-membered monocyclic or fusedbicyclic heteroaryl)-methyl, wherein said heteroaryl is optionallysubstituted with one or two substituents, each independently selectedfrom the group consisting of phenyl, C₃-C₇ cycloalkyl, —(C₁-C₃alkyl)-phenyl, and 5- to 7-membered monocyclic heterocyclyl, and whereinsaid phenyl either alone or in —(C₁-C₃ alkyl)-phenyl, cycloalkyl, orheterocyclyl is optionally substituted with one or two substituents,each individually selected from the group consisting of C₁-C₃ alkyl,halogen, and hydroxy.
 20. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is


21. The compound of claim 20, or a pharmaceutically acceptable saltthereof, wherein R^(4c) is selected from the group consisting ofhydrogen, methyl, isopropyl, —CH₂OH, —CH₂OC(CH₃)₃, and —CH₂CH₂SCH₃; andR^(4d) is selected from the group consisting of hydrogen and methyl; or,R^(4c) and R^(4d) taken together with the atom to which each is attachedform a cyclopropyl ring.
 22. The compound of claim 21, or apharmaceutically acceptable salt thereof, wherein R^(4c) and R^(4d) areeach hydrogen.
 23. The compound of claim 20, or a pharmaceuticallyacceptable salt thereof, wherein R^(4b) is hydrogen.
 24. The compound ofclaim 20, or a pharmaceutically acceptable salt thereof, wherein R^(4a)is C₁-C₆ alkyl.
 25. The compound of claim 24, or a pharmaceuticallyacceptable salt thereof, wherein R^(4a) is methyl, ethyl, isopropyl,tert-butyl, or 3-methylpentan-3-yl.
 26. The compound of claim 20, or apharmaceutically acceptable salt thereof, wherein R^(4a) is phenyl,optionally substituted with one or two substituents, each independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃alkyl, hydroxy, C₁-C₃ alkoxy, C₃-C₇ cycloalkyl, and 5- to 10-memberedmonocyclic or fused bicyclic heterocyclyl.
 27. The compound of claim 20,or a pharmaceutically acceptable salt thereof, wherein R^(4a) is: 5- to10-membered monocyclic or fused bicyclic heteroaryl, optionallysubstituted with one or two substituents, each independently selectedfrom the group consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl,hydroxy, C₁-C₃ alkoxy, C₃-C₇ cycloalkyl, and 5- to 10-memberedmonocyclic, fused bicyclic, or spiro heterocyclyl; C₃-C₇ cycloalkyl,optionally substituted with one or two substituents, each independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃alkyl, hydroxy, C₁-C₃ alkoxy, C₃-C₇ cycloalkyl, and 5- to 10-memberedmonocyclic or fused bicyclic heterocyclyl or, 4- to 10-memberedmonocyclic or fused bicyclic heterocyclyl, optionally substituted withone or two substituents, each independently selected from the groupconsisting of halogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl, hydroxy, C₁-C₃alkoxy, oxo, C₃-C₇ cycloalkyl, and 5- to 10-membered monocyclic or fusedbicyclic heterocyclyl.
 28. The compound of claim 20, a pharmaceuticallyacceptable salt thereof, wherein R^(4a) is (C₆-C₁₀ monocyclic or fusedbicyclic aryl)-C₁-C₃ alkyl or (5- to 10-membered monocyclic or fusedbicyclic heteroaryl)-C₁-C₃ alkyl, optionally substituted with one or twosubstituents, each independently selected from the group consisting ofhalogen, C₁-C₆ alkyl, halo-C₁-C₃ alkyl, hydroxy, C₁-C₃ alkoxy, C₃-C₇cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclicheterocyclyl.
 29. The compound of claim 20, or a pharmaceuticallyacceptable salt thereof, wherein R^(4a) is selected from the groupconsisting of hydroxy-C₁-C₆ alkyl, halo-C₁-C₃ alkyl, C₁-C₃ alkoxy-C₁-C₆alkyl, and —C₁-C₆ alkyl-NR^(J1)R^(J2), wherein R¹ and R² are eachindependently hydrogen or C₁-C₃ alkyl.
 30. The compound of claim 29, ora pharmaceutically acceptable salt thereof, wherein R^(4a) is selectedfrom the group consisting of —C(CH₃)₂CH₂OH, —CH₂CH₂OH, —C(CH₃)₂CH₂OCH₃,—CH(CH₃)CH₂OH, —CH₂CH₂N(CH₃)₂, and —CH₂CF₃.
 31. The compound of claim20, or a pharmaceutically acceptable salt thereof, wherein R^(4a) andR^(4b) taken together with the atom to which each is attached form a 5-to 10-membered monocyclic, fused bicyclic, or bridged bicyclicheterocyclyl, optionally substituted with one or two substituents, eachindependently selected from the group consisting of halogen, C₁-C₆alkyl, halo-C₁-C₃ alkyl, hydroxy, and C₁-C₃ alkoxy.
 32. The compound ofclaim 20, or a pharmaceutically acceptable salt thereof, wherein R^(4b)and R^(4c) taken together with the atom to which each is attached form a5- to 7-membered monocyclic heterocyclyl, optionally substituted withone or two substituents, each independently selected from C₁-C₃ alkyl.33. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁴ is

wherein R⁴⁹ is selected from the group consisting of C₆-C₁₀ monocyclicor fused bicyclic aryl and C₁-C₃ alkyl.
 34. The compound of claim 1, ora pharmaceutically acceptable salt thereof, selected from the groupconsisting of: Com- pound No. Structure 5

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and 509


35. A pharmaceutical composition comprising a compound according toclaim 1 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.
 36. A method of inhibiting irontransport mediated by ferroportin in a subject, comprising administeringto the subject an effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 37. A compound of formula:


38. A compound of formula:

or a pharmaceutically acceptable salt thereof.
 39. A compound offormula:


40. A compound of formula:

or a pharmaceutically acceptable salt thereof.
 41. A pharmaceuticalcomposition comprising a compound according to claim 37, and apharmaceutically acceptable excipient.
 42. A pharmaceutical compositioncomprising a compound according to claim 38, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.43. A pharmaceutical composition comprising a compound according toclaim 39, and a pharmaceutically acceptable excipient.
 44. Apharmaceutical composition comprising a compound according to claim 40,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 45. A method of inhibiting iron transport mediatedby ferroportin in a subject, comprising administering to the subject aneffective amount of a compound of claim
 37. 46. A method of inhibitingiron transport mediated by ferroportin in a subject, comprisingadministering to the subject an effective amount of a compound of claim38, or a pharmaceutically acceptable salt thereof.
 47. A method ofinhibiting iron transport mediated by ferroportin in a subject,comprising administering to the subject an effective amount of acompound of claim
 39. 48. A method of inhibiting iron transport mediatedby ferroportin in a subject, comprising administering to the subject aneffective amount of a compound of claim 40, or a pharmaceuticallyacceptable salt thereof.